Targeted Degradation of the c-Myc Oncoprotein: Molecular Mechanisms, Technological Platforms, and Therapeutic Perspectives in Oncology

Abstract

Background/Objectives: The c-Myc oncoprotein is a master regulator of cell cycle progression, cellular metabolism, and ribosome biogenesis, and its dysregulation occurs in more than 70% of human malignancies. Its intrinsically disordered structure and absence of deep hydrophobic binding pockets have historically limited direct pharmacological targeting, leading to its classification as an “undruggable” protein. Targeted protein degradation offers strategies to reduce c-Myc abundance by recruiting endogenous degradation machinery or introducing an exogenous protease. Methods/Results: This review evaluates recent strategies for reducing c-Myc abundance—classified into direct c-Myc degraders, indirect destabilization pathways, and proposed platform adaptations—encompassing established small-molecule modalities, including heterobifunctional proteolysis-targeting chimeras (PROTACs) and molecular glues, oligonucleotide-based PROTACs, proteomimetic polymers, MIDN-dependent ubiquitin-independent proteasomal degraders, and orthogonal bacterial proteases. Adaptable platforms, including KRAS-directed TKD constructs and anti-c-Myc modular nanotransporters (MNTs), are discussed separately because c-Myc degradation has not yet been demonstrated for these adaptations. Conclusions: Collectively, these approaches broaden the potential of c-Myc-targeted degradation to address therapeutic resistance, influence the tumor immune microenvironment, and facilitate the clinical translation of intranuclear degraders.

1. Introduction: c-Myc Oncogenicity and the “Undruggability” Paradigm

C-Myc is among the most important yet challenging targets in modern molecular oncology [1,2]. Encoded by the proto-oncogene MYC, this transcription factor serves as a global regulator of gene expression, influencing approximately 15% of the human genome [1,2]. It coordinates core cellular processes, including cell cycle progression, metabolic reprogramming, ribosome biogenesis, differentiation, and apoptosis [1,2].

Dysregulated or elevated c-Myc expression occurs in more than 70% of human malignancies [3,4]. These include aggressive solid tumors, such as breast, prostate, ovarian, pancreatic, and colorectal cancers, as well as hematologic malignancies, including Burkitt lymphoma, acute myeloid leukemia, and T-cell acute lymphoblastic leukemia [3,4]. High c-Myc expression is associated with poor clinical outcomes, increased metastatic potential, and resistance to conventional chemotherapy and targeted therapies [3,5].

Felsher and Bishop convincingly demonstrated the oncogenic role of c-Myc and the potential to reverse malignant disease by suppressing its expression [6]. Using transgenic mice with conditionally regulated c-Myc expression in hematopoietic cells, they showed that sustained oncoprotein expression induced T-cell lymphomas and acute myeloid leukemia [6]. Conversely, c-Myc suppression triggered rapid tumor regression, accompanied by proliferative arrest, differentiation, apoptosis, and restoration of normal hematopoiesis [6]. These findings established the concept of oncogene addiction and stimulated the development of targeted approaches that inhibit c-Myc activity or promote its physical elimination [7].

Embryonic knockout and antisense studies demonstrate an essential role for MYC during early development [8,9]. The consequences of c-Myc suppression in adult tissues depend on their proliferative state and on the depth, duration, and mode of intervention [7,10]. Evidence supporting this therapeutic window came from studies of systemic expression of Omomyc, a dominant-negative c-Myc peptide [10]. In the mouse model studied, reversible Omomyc expression induced tumor regression and affected proliferating normal tissues; these normal-tissue effects were reversible after Omomyc withdrawal under the experimental conditions tested [10]. As of 19 October 2026, ClinicalTrials.gov listed the Phase II pilot study of OMO-103 in advanced high-grade osteosarcoma (NCT06650514) as “Recruiting”; the record was last updated on 10 January 2025 [11]. These findings support further investigation of a therapeutic window for c-Myc targeting, while safety and recovery must be evaluated for each modality, tissue, and dosing regimen [7,10,12]. Genetic deletion, functional inhibition, and targeted degradation should not be assumed to have equivalent effects on normal tissues. Although numerous reviews have addressed approaches to targeting c-Myc [3,7,12,13,14,15,16], targeted degradation of the oncoprotein has emerged as a particularly promising strategy.

Despite the strong biological rationale for targeting c-Myc, the protein was long considered “undruggable” [3,15]. This designation reflects its distinctive biophysical properties. Unlike conventional enzymes or receptors, c-Myc is an intrinsically disordered protein [3,17]. As a monomer, it lacks a stable tertiary structure and well-defined hydrophobic pockets that enable high-affinity binding by conventional small molecules [3]. Its biological activity depends on protein–protein interactions, notably heterodimerization with the obligate partner MAX through the bHLH-LZ domain, followed by binding to E-box regulatory DNA sequences (5′−CACGTG−3′) [17,18]. These structural features complicate the development of small molecules that selectively disrupt c-Myc interactions [19].

The emergence of targeted protein degradation (TPD) has fundamentally shifted this paradigm [20,21,22,23]. Rather than sterically blocking active sites, TPD seeks to remove the target protein from the cell. By artificially recruiting a target protein to intracellular proteolytic machinery, including the ubiquitin–proteasome system (UPS) or lysosomal pathways, small molecules such as PROTACs and molecular glues, as well as biomacromolecules, can induce its destruction [20,21,22,23]. Event-driven degradation can permit repeated target turnover without sustained target occupancy [20,23].

2. Biological Basis of c-Myc Stability, Domain Organization, and Endogenous Turnover

2.1. Structural Architecture and Regulatory Domains

In normal cells, c-Myc has an extremely short half-life of approximately 20–30 min, enabling a dynamic transcriptional response to mitogenic signals [1,24]. The c-Myc protein comprises three main functional domains (Table 1) [2,4].

Table 1. Domain architecture of the c-Myc protein and regulatory functions of its domains.

Domain/Region	Structural Characteristics	Biological Role and Regulated Processes	References
N-terminal transactivation domain (TAD)	Intrinsically disordered region containing Myc boxes (MB0, MBI, MBII)	Recruitment of transcriptional coactivators and chromatin remodelers; regulation of degradation via MBI phosphorylation (Thr58/Ser62)	[1,2,4]
Central modulatory domain	Contains conserved MBIII and MBIV regions	Involvement in apoptosis induction, neoplastic transformation, and mRNA stability regulation	[2,4]
C-terminal bHLH-LZ domain	Basic helix–loop–helix and leucine zipper	Heterodimerization with the MAX protein; site-specific binding to E-box DNA motifs (5′−CACGTG−3′)	[17,18]

The key molecular switch governing c-Myc stability is the MBI region within the TAD [1]. It contains threonine 58 (Thr58) and serine 62 (Ser62) residues [1]. Initial phosphorylation of Ser62 by kinases of the MAPK or CDK families stabilizes the protein [1]. Subsequent phosphorylation of Thr58 by glycogen synthase kinase 3 (GSK-3β) creates a consensus phosphodegron that triggers Ser62 dephosphorylation and subsequent proteasomal degradation [1].

2.2. Natural Degradation Pathways via the UPS

The principal mechanism of c-Myc clearance is ubiquitin-dependent proteolysis by the 26S proteasome, which is regulated by several E3 ubiquitin ligases [1]:

• Fbw7 ligase (SCF^Fbw7): A classical tumor suppressor that specifically recognizes the Thr58-phosphorylated MBI motif [1]. Fbw7 ubiquitinates c-Myc during the G1 phase [1,25]. Mutations in the FBXW7 gene or in the c-Myc phosphodegron, which are characteristic of lymphomas, block proteolysis and cause pathological hyperstabilization of the oncoprotein [1].
• Skp2 ligase (SCF^Skp2): Acts during the S phase of the cell cycle [1]. Skp2 promotes c-Myc degradation while simultaneously acting as a transcriptional coactivator of its oncogenic activity [1].
• CHIP ligase (U-box type): Functions in the chaperone-mediated protein quality-control system in conjunction with Hsp70/90 [1,18,26]. CHIP can directly interact with c-Myc and target it for degradation, providing a basis for the design of chimeric degraders [1,18,26].
• UBE3B promotes c-Myc ubiquitination and proteasomal turnover through a pathway that can operate independently of Fbw7 but remains dependent on c-Myc Thr58 phosphorylation. c-Myc-T58A substitution reduced UBE3B binding and ubiquitination, while GSK3 inhibition attenuated UBE3B-mediated c-Myc ubiquitination. UBE3B depletion increased c-Myc stability, and Ube3b deletion shortened survival in c-Myc-driven lymphoma mouse models [27].

2.3. The Role of the TRIB3–Myc Axis in Protection from Degradation

An important regulator of c-Myc stability is Tribbles Pseudokinase 3 (TRIB3) [28]. TRIB3 binds to c-Myc and interferes with its interaction with UBE3B, thereby reducing UBE3B-mediated ubiquitination and degradation [27]. This interaction increases c-Myc stability and enhances its transcriptional activity in complex with MAX [28]. Genetic depletion or pharmacological inhibition of TRIB3 reduces intracellular c-Myc levels, suppresses target-gene expression, and inhibits the proliferation of B-cell lymphomas and solid carcinomas [28]. The development of helical peptides and small molecules that bind to the Glu344 pocket of TRIB3, as well as PROTAC chimeras designed to eliminate TRIB3, represents a promising strategy that shows pronounced synergy with BET inhibitors, CDK7 inhibitors, and DNA-damaging agents [28].

3. TPD Technology Platforms: PROTACs, Molecular Glues and Structural Barriers

3.1. Mechanisms of Action: PROTACs vs. Molecular Glues

Two major small-molecule approaches to ubiquitin-dependent targeted degradation are heterobifunctional PROTACs and molecular glue degraders (MGDs) [20,22]. Both platforms employ the principle of proximity-induced pharmacology but differ in their structural architecture and pharmacodynamics (Table 2) [20,22].

Table 2. Comparative characteristics of PROTAC platforms and molecular glues.

Parameter	PROTAC Chimeras	Molecular Glues (MGDs)	References
Structure	Bifunctional (two active moieties)	Compact monovalent	[20,21,22]
Linker	Required; critical for ternary complex conformation	Absent	[22,23]
Molecular weight	Typically 700–1200 Da; not a defining range	Often <500 Da; not a defining limit	[22,23]
Bioavailability	Often limited by size and polarity; compound-dependent	Potentially favorable oral exposure; compound-dependent	[22,23]
Blood–brain barrier permeability	Often limited by size and polarity; optimization or delivery strategies may be required	CNS penetration requires compound-specific demonstration	[22]
Mechanism of action	Formation of a ternary complex via a spacer	Induction or stabilization of productive target–ligase interactions	[20,21,22,23]

• PROTAC chimeras: These consist of three structural modules: a ligand for the target protein (warhead), a flexible or conformationally rigid chemical linker, and a ligand that binds to an E3 ubiquitin ligase or its substrate receptor, such as cereblon (CRBN), von Hippel–Lindau tumor suppressor (VHL), or an inhibitor of apoptosis protein [20,23]. A PROTAC recruits the protein of interest (POI) to an endogenous E3 ubiquitin ligase, forming a ternary complex [POI–PROTAC–E3] by orienting the target protein relative to the ligase to enable polyubiquitin transfer to lysine residues [23,29,30]. Complex dissociation can release the PROTAC for subsequent degradation cycles [23,31].
• Molecular glues (MGDs): These small molecules induce or stabilize interactions between a target protein and an E3 ligase or its associated machinery, promoting target ubiquitination and degradation without the modular target-ligand–linker–E3-ligand architecture of classical PROTACs [22].

3.2. Incomplete c-Myc Depletion and N-Terminal Truncation: The MTP3 Example

MTP3 illustrates that treatment with an MYC-targeting PROTAC can produce outcomes beyond complete target elimination [19]. MTP3 was synthesized from a modified KJ-Pyr-9 ligand and a ligand that recruits CRBN, the substrate receptor of the CRL4 E3 ubiquitin ligase complex, and selectively bound to c-Myc [19]. However, rather than undergoing complete degradation, c-Myc accumulated as an N-terminally truncated variant, tMyc [19].

The tMyc fragment lacks approximately 10 kDa of the N-terminal transactivation domain but fully retains the C-terminal bHLH-LZ domain [19]. Consequently, tMyc continues to bind to MAX and DNA and retains its ability to promote cancer cell proliferation [19]. The accumulation of functionally active tMyc indicates that treatment can result in incomplete c-Myc degradation [19]. Proteasomal degradation requires substrate engagement, unfolding, and translocation into the proteolytic core. Limitations at one or more of these steps may contribute to the formation of truncated products; however, the specific contributions of substrate geometry, MAX binding, and proteasomal engagement remain to be established. These findings underscore the importance of assessing both full-length c-Myc depletion and the persistence of biologically active fragments when evaluating c-Myc-directed degraders.

4. Direct Approaches to c-Myc Degradation

4.1. WBC100: A Small-Molecule c-Myc Degrader with a Proposed Molecular Glue Mechanism

An important step in the clinical exploration of c-Myc TPD was the synthesis and early-stage evaluation of a water-soluble derivative of the natural product triptolide, 14-D-valyl-triptolide (WBC100) [32,33].

WBC100 binds to the NLS1–Basic–NLS2 region of c-Myc and promotes its proteasomal degradation [32]. Treatment increased the association of c-Myc with CHIP and Hsp70, while pull-down experiments with purified CHIP supported direct compound–ligase binding. CHIP knockdown attenuated c-Myc depletion, supporting a role for this E3 ligase [32]. A post-translational degradation mechanism is supported by early MYC mRNA measurements, increased c-Myc ubiquitination, and rescue by the proteasome inhibitor MG132 [32]. In cycloheximide (CHX)-chase assays in MOLM-13 and H9 cells, WBC100 reduced the estimated c-Myc protein half-life from approximately 55 to 31 min and from 50 to 32 min, respectively [32]. These findings support the proposed molecular glue mechanism; however, the study did not establish the structure or binding cooperativity of a c-Myc–WBC100–CHIP ternary complex [32]. In preclinical models, oral administration of WBC100 caused regression of acute myeloid leukemia (AML) patient-derived tumor xenografts in NSG mice, as well as cell line-derived xenografts of MOLM-13 (AML), MIA PaCa-2 (pancreatic cancer), and MGC-803 (gastric cancer) [32].

Clinical evidence is currently limited to an early, uncontrolled Phase I clinical trial (NCT05100251) reported in an ASCO 2025 abstract, which involved 28 patients with advanced solid tumors refractory to standard therapies [33]. The drug was administered orally every other day at doses of 0.5–3.5 mg, and the maximum tolerated dose was not reached [33]. Among the 19 evaluable patients, one patient with pancreatic ductal adenocarcinoma had a partial response, while six (31.6%) evaluable patients, including those with liver and pancreatic cancer, achieved stable disease [33]. These early observations from a small, uncontrolled cohort do not establish clinical efficacy or a broadly favorable safety profile [33]. As of 19 October 2026, ClinicalTrials.gov listed NCT05100251 as “Terminated” following the sponsor’s decision to change its development strategy; the every-other-day dosing cohort had been completed. The record was last updated on 17 February 2026. This registry status alone does not establish toxicity or lack of activity [34].

4.2. Dual Degraders Targeting the c-Myc/GSPT1 Oncogenic Axis

An innovative TPD strategy involves the development of dual degraders that simultaneously target c-Myc and the translation termination factor GSPT1 (eRF3a) [35,36,37]. GT19715 was described in earlier reports as the salt form of GT19630 [35,36]. Mechanistic studies focused on GT19630, which was developed by structurally optimizing the c-Myc:MAX inhibitor GT19077 and the CRBN ligand GT19406 [37]. In a homogeneous time-resolved fluorescence (HTRF) assay assessing CRBN binding, GT19630 showed an IC₅₀ of 26.9 nM [37]. Biochemical binding assays and cellular target-engagement experiments supported direct interaction between GT19630 and c-Myc. Cryo-electron microscopy resolved a DDB1–CRBN–GSPT1–GT19630 complex, providing structural evidence for GSPT1 recruitment. However, a corresponding c-Myc-containing complex was not structurally resolved, leaving the geometry of c-Myc recruitment unestablished [37].

The rationale for dual targeting is supported by a positive regulatory relationship between c-Myc and GSPT1: c-Myc promotes GSPT1 transcription, whereas GSPT1 contributes to proper termination of MYC mRNA translation [37].

GT19630 reduced c-Myc and GSPT1 protein levels in responsive hematologic models, with concentration- and time-dependent effects demonstrated in the experimental systems examined. Responses were not uniform; for example, resistant Raji cells exhibited GSPT1 depletion without a corresponding reduction in c-Myc. A separate viability screen evaluated GT19630 across more than 90 cell lines [37]. In GT19630-treated cells, c-Myc stop-codon readthrough, activation of the integrated stress response, and metabolic alterations affecting oxidative phosphorylation and the tricarboxylic acid cycle were observed [37]. These findings indicate effects on both protein homeostasis and cellular metabolism, although the individual contributions of c-Myc depletion, GSPT1 depletion, and downstream stress responses remain to be fully resolved. Proteasome inhibitors rescued c-Myc protein levels in GT19630-treated HL-60 cells, whereas CRBN knockout abrogated treatment-induced cell death. Comparison with the GSPT1-directed molecular glue CC-90009 supported an effect on c-Myc beyond that attributable to GSPT1 depletion alone [37]. Nevertheless, concurrent effects on c-Myc translation and protein turnover complicate quantitative attribution of the reduction in c-Myc abundance to degradation versus altered synthesis.

Early reports showed that GT19715 induced cell death in AML models irrespective of TP53 status, reduced circulating tumor cells in a systemic Daudi lymphoma model, and decreased leukemia burden in a chemotherapy-resistant AML patient-derived xenograft model [35,36]. Subsequent studies evaluated GT19715 in T-cell acute lymphoblastic leukemia and relapsed/refractory T-cell prolymphocytic leukemia models [38,39]. GT19715 was also investigated in FLT3-amplified, midostaurin-resistant AML cells [40].

Separately, GT19630 demonstrated antitumor activity in systemic Daudi lymphoma, subcutaneous HL-60 and MM.1S xenografts, and a chemotherapy-refractory AML patient-derived xenograft model [37]. GT19630 pretreatment restored venetoclax sensitivity in resistant MV4;11 cells in vitro. In mice bearing venetoclax-sensitive or -resistant MV4;11 leukemia, GT19630 reduced leukemia burden and prolonged survival [37].

In the GT19630 study, treatment at 3 mg/kg reduced white blood cell counts in CRBN^I391V mice with humanized CRBN, whereas hemoglobin and platelet levels were not reduced under the tested conditions [37]. Potential resistance determinants included reduced CRBN expression in resistant HL-60 cells and the c-Myc-T58I mutation identified in Raji cells, although their contributions require further characterization. GT19630 also showed greater cytotoxic activity against primary CD34+ AML cells than against normal hematopoietic stem/progenitor cells in experiments involving AML samples from 10 patients and normal bone-marrow samples from five donors [37]. Earlier GT19715 reports likewise described differential in vitro sensitivity between malignant cells and normal hematopoietic progenitors [35,36]. These findings support further investigation of a therapeutic window, but do not establish a clinical therapeutic index.

4.3. Oligonucleotide PROTACs

The natural DNA-binding activity of c-Myc has enabled the design of hybrid nucleic acid–chemical degraders [41,42,43].

4.3.1. TNA–E-Box–Pomalidomide (TEP)

A bivalent chimera synthesized by Li et al. combines a threose nucleic acid (TNA)–DNA recognition element with pomalidomide, a CRBN recruiter [41]. In Hs578T and 4T1 triple-negative breast cancer cells, TEP induces c-Myc reduction and growth inhibition, sensitizing cells to palbociclib [41]. In mouse allograft models using the 4T1 breast cancer cell line, intratumoral injection of liposomes containing TEP caused tumor regression when evaluated as a combination treatment with palbociclib; however, this combination efficacy cannot be assigned exclusively to TEP-mediated c-Myc degradation [41].

4.3.2. ProMyc and Bispecific circPA1-ProMyc

The ProMyc construct developed by Wang et al. links the c-Myc-binding DNA aptamer MA9C1 to pomalidomide [42]. To promote receptor-directed delivery, circPA1-ProMyc was developed as a circular chimera carrying an additional PA1 aptamer targeting Programmed Death-Ligand 1 (PD-L1) [42]. In transfected HCT116 cells, ProMyc yielded a DC₅₀ of 5.02 nM and approximately 95% loss at 50 nM after 24 h, whereas the A549 DC₅₀ was approximately 98.52 nM (HeLa and MDA-MB-231 cells were also evaluated) [42]. c-Myc/CRBN association, ligand competition, ubiquitination assays, MG132/MLN4924 rescue experiments, and CRBN genetic manipulation support involvement of the UPS [42]. However, unchanged MYC mRNA levels do not exclude a translational contribution, and accompanying MAX loss limits exclusive-target claims [42]. This design enabled selective endocytosis in PD-L1-positive tumor cells, and peritumoral administration of circPA1-ProMyc in BALB/c nude mice bearing HCT116 xenografts (5 mg/kg every four days) suppressed growth of HCT116 xenografts under the tested local dosing regimen [42].

4.3.3. Deoxyoligonucleotide PROTACs (MP-16 and MP-17)

MP-16 and MP-17 were developed as approximately 10-kDa DNA–VH032 PROTACs containing a shortened E-box duplex conjugated to a ligand for the VHL E3 ligase [43]. Electrophoretic mobility shift assays support c-Myc/MAX recognition, while biochemical pull-down assays support VHL-complex recruitment, although a proposed c-Myc homodimer explanation for c-Myc-only pull-down has not been directly demonstrated [43]. In transfected SK-Hep-1 and SNU-398 cells treated at 0.4 μM, c-Myc loss begins by 4 h, is strongest near 8 h, and weakens by 24 h [43]. VH032 competition, inactive E-box mutants, accelerated CHX-chase assays, MG132 rescue, unchanged mRNA levels and increased c-Myc ubiquitination provide substantial mechanistic support [43]. In female BALB/c nude mice bearing subcutaneous SNU-398 tumors, PEI-formulated MP-16 or MP-17 was administered intravenously at 5 or 10 mg/kg every other day. Approximately 50% tumor growth inhibition and reduced tumor c-Myc were reported [43]. Limited organ histology and biochemical measurements support tolerability under these conditions [43].

4.4. Heterobifunctional Proteomimetic Copolymers (HYDRACs)

Wang et al. developed macromolecular degraders termed Hybrid Degrading Copolymers (HYDRACs) built on a ring-opening metathesis polymerization (ROMP)-derived norbornene polymer backbone [17]. HYDRACs are assembled modularly from a target-binding peptide ligand (e.g., the c-Myc-binding H1 peptide), cationic elements, and a C-terminal RRRG peptide degron designed to promote proteasomal recruitment, enabling multivalent binding to conformationally labile oncoproteins [17]. In PC3 cells, endogenous c-Myc reduction was detectable at 0.3 μM after 24 h. Separately, c-Myc-T58A decreased in engineered PC3 cells treated with 2.5 or 5 μM for 6 h. Sustained c-Myc suppression after washout was assessed following 10 μM treatment for 24 h, with monitoring for a further 72 h [17]. The sustained reduction in c-Myc after washout indicates a prolonged cellular effect but does not, by itself, establish repeated degradation cycles by the same HYDRAC molecule [17]. MG132/MLN4924 rescue supports proteasome- and neddylation-dependent activity; the E3 machinery underlying RRRG-mediated degradation remains unresolved. Separate c-Myc-directed variants incorporated VHL, Keap1, or CRBN recruiters. KRAS degradation was achieved using distinct KRAS-targeting HYDRACs [17]. In immunocompetent FVB mice bearing subcutaneous MycCaP prostate allografts, intraperitoneal (i.p.) HYDRAC administration (25 mg/kg three times weekly for 25 days) achieved 52% tumor growth inhibition (TGI), accompanied by reduced Ki67 expression and increased cleaved caspase-3 in tumor tissue, without detectable body-weight loss. In healthy mice, single intraperitoneal doses of MYC-targeting HYDRACs up to 40 mg/kg were associated with minimal histopathological changes [17]. In Luc-MV4-11 models, IVIS imaging following administration of Cy5.5-labeled HYDRAC showed tumor-associated fluorescence for up to 72 h, with minor hepatic and renal signals [17].

4.5. Ubiquitin-Independent Degradation via Midnolin (MbTAC and the c-Myc-Directed Peptide MbMD)

A major limitation of classical PROTACs is their dependence on ubiquitination: mutations in ligase receptors (CRBN, VHL) can confer primary resistance to therapy [20,22]. Zhao et al. proposed a strategy to circumvent this resistance by developing MbTACs (midnolin-based targeting chimeras), which function independently of ubiquitin [44]. This mechanism is based on the nuclear protein midnolin (MIDN), which binds to short-lived transcription factors through a conserved Catch domain and directs them for proteasomal degradation [44]. The MbTAC construct is a multifunctional peptide comprising the following components [44]:

(a)

A c-Myc-binding module;

(b)

A midnolin-binding module (KLVFF peptide);

(c)

A proteolytically cleavable linker specifically cleaved by the tumor-associated protease legumain;

(d)

A cell-penetrating peptide.

Intracellular c-Myc/MIDN engagement by MbMD is supported by nuclear colocalization, subcellular fractionation, co-immunoprecipitation (co-IP), NanoBRET, and binding-defective mutant controls [44]. Furthermore, the proteasome inhibitor MG132 attenuates c-Myc loss, the E1 ubiquitin-activating enzyme inhibitor TAK-243 fails to block degradation under the tested conditions, and MIDN genetic knockout abolishes the effect, collectively supporting MIDN-dependent, ubiquitin-independent proteasomal degradation [44]. In HCT116, PC-3, and SK-OV-3 cells, MbMD induced proteasomal degradation of c-Myc [44], yielding reported 24-h DC₅₀ values of 5.483 μM, 4.451 μM, and 12.35 μM, respectively [44]. Importantly, these quantitative DC₅₀ values derive from plasmid-expressed HiBiT–c-Myc rather than an endogenous knock-in reporter, whereas endogenous c-Myc depletion was confirmed separately by immunoblotting across 12, 24, and 48 h time courses at 10 μM [44]. Additional antiproliferative activity was observed across SNU119, 769-P, A2780, and MDA-MB-231 cell lines, which served as viability models rather than quantitative degradation models [44]. In vivo, intravenous administration of MbMD to male nude mice bearing HCT116 xenografts at 10 mg/kg every other day (n = 5; endpoint at day 16) suppressed tumor growth and reduced intratumoral c-Myc abundance, demonstrating the feasibility of ubiquitin-independent degradation of nuclear oncoproteins [44].

4.6. MYC-LYSO and Se-MYC-LYSO

The use of generative structural AI has enabled the design of peptide agents that promote lysosomal degradation via chaperone-mediated autophagy (CMA) [45]. Based on the c-Myc/MAX dimer structure, Liu et al. designed a bifunctional peptide degrader, MYC-LYSO, which incorporates a peptide dimerization inhibitor and a CMA-targeting signal, whereas the Se-MYC-LYSO formulation incorporates selenium nanoparticles as a delivery platform [45]. Across cellular models including DU145, C4-2, CWR22Rv1, and HeLa cells, the degrader directs c-Myc to the lysosomal compartment and induces apoptosis, with lysosomal-pathway and LAMP2A controls supporting CMA involvement [45].

4.7. Max-CHIP

Hatakeyama et al. developed the artificial E3 ubiquitin ligase Max–CHIP (Max-U) by genetically fusing the c-Myc-binding MAX element to the catalytic U-box-containing region of CHIP [18]. Experiments in HEK293T, HeLa, NIH3T3, and Namalwa cells, including a catalytically impaired P270A control, support c-Myc polyubiquitination and proteasomal degradation. Expression of the fusion reduced c-Myc stability and suppressed colony formation in agar. Because Max–CHIP contains its own E3 catalytic module, its activity does not require recruitment of endogenous CHIP. In vivo, implantation of engineered NIH3T3-Myc/Bcl2 cells expressing Max–CHIP into BALB/c nude mice resulted in reduced tumor development. This experiment provides proof of principle for suppression of tumorigenicity, but does not establish therapeutic efficacy of a systemically administered Max–CHIP agent [18].

4.8. Direct Orthogonal Proteolysis by the Bacterial Lon Protease (rLon)

An alternative approach to c-Myc targeting uses recombinant bacterial Lon (rLon), an ATP-dependent serine protease from Escherichia coli, as an orthogonal proteolytic tool [46,47]. Unlike agents that recruit endogenous degradation machinery, rLon can directly cleave c-Myc without requiring a host E3 ubiquitin ligase, substrate ubiquitination, or the 26S proteasome. Purified-protein assays and experiments in A498 cells support this mechanism [46,47]. However, the reported local efficacy in animal models does not establish systemic delivery to distant tumors or the absence of host immunogenicity against this bacterial enzyme.

The effects of rLon involve both direct proteolysis and inhibition of c-Myc function. Lon recognizes and cleaves intrinsically disordered, serine-rich regions of c-Myc, compromising structural elements required for DNA binding and interaction with MAX. Separately, the N-terminal domain of Lon binds to the C-terminal regions of c-Myc and MAX with reported submicromolar affinity (K_d < 1 μM), interfering with c-Myc/MAX complex formation and E-box binding. These inhibitory effects, and associated changes in transcription, should be distinguished from destruction of the target protein. Because direct Lon-mediated proteolysis does not require the canonical Thr58–Fbw7 pathway, it may circumvent resistance arising from defects in this pathway [46,47]. Preclinical studies in MB49 bladder tumor models using intravesical administration and in ApcMin intestinal tumor models using oral administration provide evidence of antitumor activity, including reduced c-Myc abundance, suppression of tumor progression, and improved survival in the investigated settings [46].

5. Indirect Pathways That Destabilize or Reduce c-Myc

Natural compounds can modulate protein stability through several mechanisms, including enhanced E3-dependent ubiquitination of target proteins and degradation of factors that normally protect other proteins from turnover. Studies of targets other than c-Myc illustrate this mechanistic diversity. Berberine has been reported to act as a molecular glue degrader that promotes TRIM28-mediated ubiquitination and degradation of HIF-1α, contributing to ferroptosis in resistant chronic myeloid leukemia models [48]. Echinacoside binds to FBXO11 and promotes its ubiquitin–proteasome-dependent degradation in colorectal cancer models. Loss of FBXO11 reduces protective K63-linked ubiquitination at Lys15 of TMBIM6, facilitating its subsequent K48-linked ubiquitination and proteasomal degradation [49]. Okanin binds to PRDX5 and promotes its WSB1-mediated ubiquitination and degradation, accompanied by reduced GPX4 expression [50]. Cathayanon E binds to MCL1 and enhances its β-TRCP-mediated ubiquitination and proteasomal degradation, increasing sensitivity to oxaliplatin in colorectal cancer models [51]. These findings illustrate how natural compounds can alter proteostasis through distinct molecular interactions. Their relevance to c-Myc destabilization, however, requires target-specific evidence, as discussed below.

With respect to c-Myc, natural small molecules can promote its degradation through several mechanisms. One such mechanism involves the N-terminal MBI phosphodegron, where priming phosphorylation at Ser62 (mediated by the Ras/ERK axis) enables subsequent Thr58 phosphorylation by GSK-3β, recognition by the Fbw7 E3 ligase, and proteolysis by the 26S proteasome [1,25]. The compounds discussed below differ in their mechanisms and in the strength of evidence for accelerated c-Myc turnover.

Oridonin, an ent-kaurane diterpenoid isolated from Rabdosia rubescens, promotes GSK3/Fbw7-associated c-Myc turnover. Experiments involving K562, KU812, HL-60, and Daudi cells include CHX-chase analysis, MG132 rescue, ubiquitination assays, MYC-mRNA measurements, and phosphodegron and genetic controls; K562 xenografts in NOD/SCID mice provide additional in vivo support [52]. These findings support indirect proteasomal destabilization rather than established direct binding to c-Myc. Oridonin also affects other oncogenic pathways, including miR-17/20a regulation and HSF1/Hsp70-associated BCR–ABL degradation, emphasizing its pleiotropic activity [53].

Antimycin A, a microbial inhibitor of mitochondrial respiratory complex III, accelerates c-Myc turnover through ROS/GSK3-associated regulation [54]. Evidence from an E-H1 reporter system and experiments involving HCT116, HeLa, MIA PaCa-2, A549, PANC-1, and HL-60 cells includes accelerated CHX-chase kinetics, increased c-Myc ubiquitination, unchanged MYC mRNA, pharmacological GSK3 controls, and relative resistance of the T58A variant. These results support indirect destabilization, but MG132-assisted accumulation of ubiquitinated c-Myc should not be equated with an independently quantified rescue of protein loss [54].

Dihydroartemisinin (DHA), an artemisinin derivative, reduces c-Myc expression in Jurkat and HuT78 cells at 15–30 μM over 48 h, alongside changes in AKT/GSK3 signaling [55]. However, MYC mRNA levels also decrease, making it difficult to unequivocally distinguish between accelerated protein degradation and reduced protein synthesis. DHA is therefore considered an indirect c-Myc-lowering agent with an unproven contribution of accelerated degradation.

Platycodin D, a triterpenoid saponin from Platycodon grandiflorum, promotes c-Myc ubiquitination and MG132-sensitive turnover in gastric cancer models, including AZ521 and NUGC3 cells, with GES1 cells used as a nonmalignant comparator. CHX-chase experiments and unchanged MYC mRNA support a post-translational contribution to protein loss [56]. Nevertheless, the required E3 ligase and direct molecular target remain unidentified.

Lanatoside C, a cardiac glycoside from Digitalis lanata, affects Wnt/β-catenin signaling and USP28-associated stabilization of c-Myc [57]. The principal mechanistic study uses MKN45 and SGC7901 cells, with additional experiments involving HN4, MCF7, HepG2, and HEK293-related systems. MG132 rescue, ubiquitination assays, and USP28 manipulation support a proteasomal contribution to c-Myc loss. The mechanistic exposure of 5 μM for 6 h should be distinguished from nanomolar concentrations affecting cell viability. A subsequent prostate-cancer study implicating TNF/IL-17 signaling broadens the reported biological effects of lanatoside C [58].

The translational potential of natural compounds requires compound-specific assessment, as bioavailability, selectivity, and tolerability vary across agents. Where such limitations are identified, structural optimization or targeted delivery strategies may help improve their therapeutic potential [53,57,58]. Rational modification of the core chemical structures of natural products through medicinal chemistry—including the introduction of thiazole and triazole heterocycles into the A-ring of oridonin (CYD0617, CYD0618), D-ring aziridination (YD0514), and the design of water-soluble prodrugs (HAO472 [53], WBC100 [32,33])—may in the future help overcome pharmacokinetic barriers and facilitate the use of natural products as starting points for developing selective degraders of oncoproteins.

6. Adaptable and Proposed Platforms for Which c-Myc Degradation Has Not Yet Been Experimentally Demonstrated

6.1. Nanobody-Mediated Lysosomal Degradation of Intracellular Regulatory Oncoproteins (TKD Platform)

Yang et al. [59] developed a new modular strategy for the destruction of intracellular oncogenic proteins and created a chimeric biodegrader, TKD (tumor-targeting KRAS degrader), that directs target proteins to the lysosomal compartment.

The construct is a recombinant polypeptide that combines three functional domains:

(a)

Cell-penetrating peptide BR2: supporting preferential uptake of TKD in the examined tumor-cell models; labeled TKD uptake was detected in HT29 and HCT116 cells but not in the FHC normal colon epithelial comparator under the tested conditions [59];

(b)

Single-domain antibody (nanobody) to KRAS: a high-affinity binding unit (K_d = 6.57 nM) with high thermal stability (T_m ≈ 78.9 °C);

(c)

Lysosomal peptide degron CTM (KFERQKILDQRFFE): a signal sequence recognized by lysosomal receptors that triggers uptake of the resulting protein complex into lysosomes for subsequent proteolysis.

The platform operates through ubiquitin-independent lysosomal degradation: degradation is completely blocked by lysosomal inhibitors (Lys05 and bafilomycin A1) but persists in the presence of the 26S proteasome inhibitor MG132 [59].

Although the platform has been validated across multiple KRAS variants, including secondary G12C inhibitor-resistance mutations (R68S, Y96C, and H95D/Q/R), TKD treatment reduced RAF/ERK signaling and c-Myc abundance in the examined models [59]. Consequently, it must be emphasized that direct experimental evidence for TKD so far concerns intracellular KRAS degradation, whereas anti-c-Myc TKD constructs represent a proposed, prospective platform extension. The authors note that this three-component paradigm could theoretically be extended to other targets: replacing the KRAS-binding nanobody with a c-Myc-binding module could provide a starting point for a c-Myc-directed construct, subject to independent validation of intracellular delivery, target engagement, and lysosome-dependent c-Myc degradation.

In addition, TKD-mediated degradation restores the transcription factor IRF2, suppresses expression of the immune checkpoint PD-L1 on the tumor cell surface, and reduces myeloid-derived suppressor cell (MDSC) infiltration, thereby synergizing with anti-PD-1 immunotherapy and the anti-EGFR monoclonal antibody cetuximab in vivo [59].

6.2. Modular Nanotransporter Technology and “Diving Antibodies”

The development of highly specific protein degraders has long been hindered by the inability of macromolecules to cross biological membranes [60]. To address this fundamental challenge, Sobolev’s group developed modular nanotransporters (MNTs)—artificial recombinant polypeptides that enable the precise intracellular delivery of bioactive molecules [61,62]. MNTs have provided the basis for a new class of targeted agents: “diving antibodies” [63,64,65,66,67,68,69,70].

Each MNT molecule comprises the following complementary modules [61,62]:

(a)

The ligand module: provides high-affinity binding to internalizable receptors on cancer cells (e.g., EGFR), thereby triggering receptor-mediated endocytosis [61,62];

(b)

The endosomolytic module: a pH-dependent peptide (e.g., a peptide derived from the diphtheria toxin translocation domain) that forms pores in the endosomal membrane during acidification, enabling MNT release into the cytosol [61,62];

(c)

The intracellular transport module: contains a canonical nuclear localization signal (NLS) from the SV40 large T antigen, enabling importin-dependent transport into the nucleoplasm [61,62];

(d)

The carrier module: stabilizes the overall three-dimensional architecture of the molecule [61,62];

(e)

Antibody mimetic: a monobody or nanobody that selectively binds to an intracellular target [65,70].

Lupanova et al. developed an MNT-based “diving antibody” containing the anti-c-Myc nanobody CMY-CVH-12-321. This “diving antibody” bound to recombinant EGFP–c-Myc (K_d = 46 ± 14 nM) and interacted with EGFR on A431 epidermoid carcinoma cells (K_d = 20.1 ± 2.1 nM) [70]. While the inclusion of an NLS motif and pH-dependent liposomal leakage assays support the design of the transport modules, they do not by themselves establish functional nuclear delivery in cells [70]. In A431 cells, 500 nM “diving antibody” reduced abundance of nucleolin protein (its gene is a c-Myc target gene) after 5 h, as assessed by Western blotting. In MCF7 cells, treatment at 500 nM for six days reduced the MTT-based measure of proliferative activity to approximately 81 ± 5% of the control MNT condition [70]. Thus, this study demonstrated binding to the model target and receptor interaction, together with cellular effects consistent with inhibition of c-Myc-associated signaling; these findings do not by themselves establish direct intracellular target engagement or MNT-mediated c-Myc protein degradation [70].

A strategic extension of this platform involves incorporating peptide motifs that recruit endogenous E3 ubiquitin ligases (e.g., Keap1, VHL, or CHIP) or other degradation factors into “diving antibodies” [63,68]. The authors previously demonstrated the effectiveness of this approach for the targeted proteasomal degradation of the intracellular SARS-CoV-2 nucleocapsid (N) protein using an MNT carrying an anti-N monobody and a Keap1-binding peptide degron [63,64,68]. The incorporation of similar degrons into anti-c-Myc “diving antibodies” could, in the future, combine antibody epitope selectivity with catalytic proteasomal degradation of c-Myc within the nucleus, potentially offering an alternative to conventional PROTACs. Figure 1 depicts proposed degradation routes for MNT-based anti-c-Myc “diving antibodies”. Our laboratory is already working on obtaining experimental data on the feasibility of implementing these mechanisms.

Figure 1. Conventional PROTAC recruitment and proposed degradation-enabled MNT. Left: a heterobifunctional PROTAC recruits a protein of interest (POI) to an E3 ligase, enabling ubiquitination and proteasomal degradation when a productive complex forms. Right: candidate MNT designs combine a delivery ligand or cell-penetrating peptide (CPP), an endosomolytic module (EM), an optional nuclear localization signal (NLS), an antibody mimetic (AbM), and a proposed proteolytic recruitment motif. R/TM denotes a recruitment/targeting motif; CTM, CMA-targeting motif; E3BP, an E3-binding peptide; MRM, a midnolin-recruiting motif; α/β-imp, importins. Dashed arrows indicate proposed steps in degradation-enabled anti-c-Myc MNT designs; c-Myc degradation by these constructs has not yet been demonstrated.

7. Comparative Evidence and Translational Limitations

Table 3 evaluates evidence for c-Myc degradation using concentration- and time-dependent protein loss; rescue by proteasomal or lysosomal inhibition, as appropriate; genetic or pharmacological validation of the recruited E3 ligase or alternative pathway; target ubiquitination for ubiquitin-dependent UPS mechanisms; and controls distinguishing accelerated turnover from reduced transcription or translation. Criteria are applied according to mechanism.

Table 3. Comparative evidence and requirements for confirming degradation.

Agent and Mechanism	Models and Efficacy	Evidence for Degradation	Delivery and Pharmacokinetics	Selectivity and Development Limitations	Evidence Level, Stage and Sources
I. Direct c-Myc-directed approaches—recognition or direct proteolysis; completeness of evidence varies
WBC100. Semisynthetic valyl-triptolide derivative; direct c-Myc binding and CHIP/Hsp70-associated UPS degradation.	MOLM-13, H9, MIA PaCa-2; AML PDX/NSG and cell-derived xenografts. c-Myc half-life: approximately 55→31 min and 50→32 min in MOLM-13 and H9.	Dose/time, CHX-chase, MG132 rescue, c-Myc ubiquitination and CHIP knockdown support turnover. Remaining validation needs: CHIP knockout/rescue.	Oral preclinical/clinical dosing. Labeled-agent uptake does not quantify active nuclear exposure; exposure–PD requires further definition.	Evidence for c-Myc-dependent activity does not establish exclusive target selectivity; additional c-Myc-independent effects remain to be excluded. Potential resistance: CHIP/Hsp70, binding site, transport. Semisynthesis requires stereochemical/impurity control.	Peer-reviewed preclinical evidence; Phase I abstract (1 PR, 6 SD among 19 evaluable patients). Registry status: Terminated (accessed 19 October 2026); clinical efficacy remains unconfirmed [32,33,34].
GT19715/GT19630. GT19630 is a GT19077-derived c-Myc ligand–CRBN PROTAC; dual c-Myc/GSPT1 effects. c-Myc engagement supported; cryo-EM resolves GSPT1, not c-Myc.	GT19630 [37]: HL-60, NB4, MOLM-13, OCI-AML3, REH, Daudi, MV4;11; AML PDX and xenografts. Tumor c-Myc PD at 24–48 h; resistant MV4;11 survival 119 vs. 37 days. Raji: GSPT1 depletion without corresponding c-Myc reduction.	GT19630 [37]: c-Myc dose/time loss and MLN9708 rescue; CRBN knockout protects cells from treatment-induced death, not a separately established c-Myc endpoint. Remaining validation needs: c-Myc ubiquitination and separation of turnover from synthesis; GSPT1/ISR confounds attribution.	GT19630 [37]: Animal exposure reported; plasma sampling differs between text/figure (4/24 h). Nuclear active-agent concentration unquantified.	GT19630 [37]: Observed low CRBN in resistant HL-60; Raji T58I association needs isogenic testing. Leukopenia in CRBNI391V mice. Synthetic PROTAC; chemistry/impurity control required.	GT19630: peer-reviewed preclinical study [37]. GT19715: conference abstracts [35,36,38,39,40], reporting it as a salt form of GT19630; equivalence of exposure and biological activity across studies has not been established. No confirmed clinical efficacy.
MTP3. KJ-Pyr-9-derived c-Myc ligand linked to a CRBN recruiter; incomplete c-Myc processing.	PC3; additional DU145, VCaP and MCF7 contexts. Micromolar exposure removes full-length c-Myc but generates active N-terminally truncated tMyc.	Remaining validation needs: quantification of both termini and functional fragments, CRBN dependence and ubiquitination. Transcript coverage analysis addressed alternative splicing; the mechanism of tMyc generation remains incompletely resolved, and full-length band loss alone does not establish complete degradation.	Cellular dosing supports access; nuclear exposure and achievable therapeutic animal PK are unestablished.	Active tMyc is an observed escape outcome; CRBN defects are plausible liabilities. Organic synthesis feasible, but delivery and molecular properties need optimization.	Peer-reviewed cellular mechanism; no established therapeutic animal efficacy. Mechanistic tool rather than validated therapeutic degrader [19].
TEP. TNA–DNA/E-box recognition element linked to pomalidomide; c-Myc/MAX-directed CRBN PROTAC.	Hs578T and 4T1; 4T1 time courses at 100 nM. Liposomal combination with palbociclib tested in 4T1 tumors.	Partial MG132 rescue and CHX support proteolysis. Remaining validation needs: genetic evidence for CRBN dependence, c-Myc ubiquitination and separation of degradation from decoy inhibition and combination effects.	Oligonucleotide entry/escape depend on formulation. TNA nuclease stability does not establish plasma PK; combination/carrier alter exposure.	c-Myc/MAX recognition limits monomer-specific claims. Potential resistance: CRBN and uptake. TNA–DNA conjugation and liposome purity/loading complicate manufacture.	Peer-reviewed preclinical cell and combination animal evidence; efficacy cannot be assigned solely to TEP-mediated c-Myc loss [41].
ProMyc/circPA1-ProMyc. MA9C1 DNA aptamer–pomalidomide; CRBN. Circular variant adds PD-L1 recognition; aptamer Kd ≈ 29.9 nM.	HCT116, A549, HeLa, MDA-MB-231. Transfected HCT116: DC50 5.02 nM, approximately 95% loss at 50 nM/24 h. HCT116 nude-mouse xenografts.	c-Myc/CRBN association, Ub, MG132/MLN4924 rescue and CRBN manipulation support the route. MAX also decreases.	Cellular potency uses transfection. circPA1: peritumoral 5 mg/kg every four days; systemic PK and autonomous nuclear uptake unestablished.	Potential resistance: CRBN, epitope, PD-L1/uptake. Manufacturing considerations: conjugation, circularization and residual linear species; exclusive c-Myc selectivity is not established.	Peer-reviewed preclinical evidence with local animal efficacy; no established systemic or clinical validation [42].
MP-16/MP-17. Approximately 10-kDa E-box DNA–VH032 PROTACs; c-Myc/MAX recognition and VHL recruitment.	Transfected SK-Hep-1/SNU-398: c-Myc loss by 4 h, strongest near 8 h, weaker at 24 h at 0.4 μM. SNU-398/BALB/c nude tumors: approximately 50% growth inhibition.	MG132 rescue, CHX, c-Myc-Ub, VH032 competition and E-box controls. Remaining gaps include VHL knockout/rescue; 0.4 μM is not DC50.	PEI formulation, IV 5 or 10 mg/kg every other day. PK and improved bioavailability from duplex shortening are not established.	MAX preserved; global proteomic selectivity unproven. Potential VHL/delivery resistance; acquired resistance untested. DNA conjugate/duplex and PEI quality control required.	Peer-reviewed mechanism and animal efficacy; limited evidence of tolerability; comprehensive toxicology remains unavailable [43].
HYDRAC. H1 c-Myc-binding peptide/cationic elements on a ROMP polymer; proteasome/neddylation-sensitive, RRRG-associated E3 unresolved; separate variants incorporate VHL, Keap1, or CRBN recruiters.	PC3, A549, MycCaP, HEK293T. In PC3: endogenous c-Myc reduction at 0.3 μM/24 h; c-Myc-T58A reduction at 2.5–5 μM/6 h. Washout: 10 μM/24 h pretreatment; suppression monitored for another 72 h. MycCaP/FVB tumors.	MG132/MLN4924 rescue supports pathway involvement. Unresolved: E3 identity for the RRRG-containing variant, c-Myc ubiquitination, E1 dependence, synthesis rates and retention of active polymer after washout.	Intraperitoneal animal dosing. Fluorescence distribution is not intact-polymer PK or nuclear concentration; persistence need not imply catalytic recycling.	Proteomics supports assessment, not universal specificity. Potential uptake/proteostasis resistance. Manufacturing considerations: molecular-weight distribution, peptide density and residual ROMP catalyst.	Peer-reviewed preclinical study. Ubiquitin-independent action is not established [17].
MbTAC/MbMD. CH1–KLVFF–CPP–AAN peptide; MIDN-dependent, ubiquitin-independent proteasomal route. MIDN Kd: 390 nM (BLI) and 156 nM (SPR); these values do not represent c-Myc affinity.	24-h plasmid HiBiT–c-Myc DC50: HCT116 5.483, PC-3 4.451, SK-OV-3 12.35 μM. Endogenous blots and HCT116 nude-mouse tumors support activity.	MG132 rescue, TAK-243 insensitivity, MIDN KO and interaction controls. Remaining validation needs: MIDN re-expression and LGMN genetic validation beyond AAN cleavage.	Nuclear fractionation/colocalization support access. IV 10 mg/kg every other day in mice. PK and metabolic stability remain undefined.	Proteomics supports selectivity in HCT116. MIDN is a causal dependency; delivery/legumain are potential liabilities. Solid-phase synthesis/HPLC/MS shown, GMP scaling untested.	Peer-reviewed main article and SI; cellular mechanism and animal efficacy. Preclinical, without clinical validation [44].
MYC-LYSO/Se-MYC-LYSO. c-Myc-directed peptide with CMA-targeting motif; selenium nanoparticle formulation.	DU145, C4-2, CWR22Rv1, HeLa; cellular c-Myc reduction and growth inhibition. Comparable DC50/Dmax/kinetics not established in the reviewed study.	Lysosomal and LAMP2A controls support CMA. Remaining validation needs: causal rescue, HSPA8 dependence, translocation, and empty Se particle controls.	Cellular delivery evidence; active nuclear-pool access, intact-peptide PK and selenium clearance require measurement. Particle size is not exposure.	Potential LAMP2A/HSPA8, lysosome and uptake liabilities. Broader selectivity unestablished. Manufacturing considerations: peptide purity and particle dispersion/loading/release. Se-related toxicity requires assessment.	Peer-reviewed cellular proof of concept; animal antitumor efficacy and plasma-stability claims are not established by the reviewed evidence [45].
Max–CHIP (Max-U). c-Myc-binding MAX fused to the catalytic CHIP region; carries its own E3 module.	HEK293T, HeLa, NIH3T3, Namalwa. Reduced c-Myc stability and agar colonies; engineered NIH3T3-Myc/Bcl2 implants in BALB/c nude mice.	Ub, proteasomal turnover and catalytic P270A control support the mechanism. Remaining validation needs: fusion-expression titration. Endogenous CHIP recruitment is unnecessary.	Intracellular expression supplies the construct. Therapeutic protein/RNA/vector delivery, nuclear exposure and finished-product PK are unestablished.	Unresolved: broader MAX-associated effects. Potential loss of expression, binding or catalytic activity. Manufacture depends on the chosen protein, RNA or vector product.	Peer-reviewed proof of principle. Engineered-cell tumorigenicity experiments do not establish efficacy of systemic drug treatment [18].
rLon. Recombinant ATP-dependent bacterial protease; direct c-Myc cleavage without host E3/Ub or 26S proteasome. Inhibition mediated by the Lon N-terminal domain is a separate effect.	Purified protein/A498; MB49 intravesical and ApcMin intestinal/oral models. c-Myc depletion and antitumor effects in local preclinical settings.	Remaining validation needs: catalytic/ATPase mutants, cleavage-product MS, intracellular localization and separation of cleavage from reduced synthesis and c-Myc/MAX inhibition; host UPS rescue is not obligatory.	Local bladder/intestine results do not establish systemic or nuclear active-enzyme exposure. Cellular entry and enzyme disposition need quantification.	Substrate breadth and immunogenicity require testing. Potential access/neutralization resistance. Manufacturing considerations: recombinant assembly, activity and endotoxin. Off-target proteolysis requires assessment.	Peer-reviewed preclinical studies. Systemic efficacy, absence of resistance and long-term safety are not established [46,47].
II. Indirect destabilization of or reduction in c-Myc expression
Oridonin. Ent-kaurane diterpenoid; indirect GSK3/Fbw7-associated c-Myc turnover; direct c-Myc binding unestablished.	K562, KU812, HL-60, Daudi; K562/NOD-SCID xenografts. Accelerated turnover and growth inhibition; no harmonized cross-platform DC50.	CHX, MG132, Ub, RNA and phosphodegron/genetic controls support turnover. Remaining validation needs: rescue with degradation-resistant, functional c-Myc.	Functional cell access; tolerable exposure–c-Myc PD and quantitative nuclear drug levels require definition. Derivative PK cannot substitute for parent PK.	Pleiotropy limits c-Myc specificity. Potential FBXW7/GSK3 or T58/S62 resistance. Natural sourcing/semisynthesis, purity and formulation need control.	Peer-reviewed cellular mechanism and animal evidence; preclinical c-Myc application, therapeutic window unresolved [52,53].
DHA. Artemisinin derivative; indirect c-Myc-lowering effects associated with signaling/transcription changes; no established c-Myc binder.	Jurkat/HuT78: c-Myc protein and mRNA decrease at 15–30 μM/48 h. No established degradation DC50 or animal validation in the study.	Proteasomal/lysosomal rescue, turnover, c-Myc-Ub and causal-pathway evidence is insufficient. The relative contributions of reduced synthesis and accelerated degradation remain unresolved.	Cell exposure does not establish sustained tumor exposure at tested concentrations. Prior use for another indication does not prove c-Myc-targeting PK.	Pleiotropic activity; potential signaling/antioxidant adaptation. Established drug-substance production does not resolve the oncology exposure or mechanism gaps.	Peer-reviewed cellular c-Myc-lowering evidence; accelerated degradation and anticancer clinical efficacy unproven [55].
Platycodin D. Triterpenoid saponin; indirect UPS-associated c-Myc destabilization, direct target/E3 unresolved.	AZ521, NUGC3, GES1 comparator; 2–15 μM/48-h experiments, c-Myc reduction and growth inhibition. No animal efficacy in the primary study.	CHX, MG132, c-Myc-Ub and stable mRNA support turnover. Remaining validation needs: E3 identification with knockout/rescue and early effects preceding broad stress.	Cell activity does not quantify nuclear delivery. c-Myc-specific intact-agent PK/PD is not established in the reviewed study.	Selectivity remains unresolved without exclusion of general proteotoxicity. Potential unknown-E3/uptake/stress resistance. The compound’s complex glycosylated structure requires control of chemical composition and formulation.	Peer-reviewed cellular mechanism; early preclinical evidence, no established therapeutic animal or clinical efficacy [56].
Lanatoside C. Cardiac glycoside; indirect USP28/Wnt-associated c-Myc regulation; no established direct c-Myc binder.	MKN45, SGC7901; additional HN4, MCF7, HepG2 and HEK293-related experiments. Mechanistic 5 μM/6 h differs from nanomolar viability endpoints.	MG132, Ub and USP28 manipulation support UPS contribution. Unresolved: E3 identity and the contributions of transcription, deubiquitination and nascent synthesis relative to Na+/K+-ATPase stress.	The relationship between tolerable active-agent exposure and c-Myc PD remains undefined; established cardiac pharmacology does not establish an oncology therapeutic window.	Pleiotropy/cardiac-glycoside liabilities; potential DUB/Wnt adaptation. Manufacturing familiarity is useful, but purity/formulation and systemic ATPase effects remain relevant.	Peer-reviewed cellular c-Myc mechanism. Later prostate-cancer findings are a separate biological context, not proof of the same pathway [57,58].
Antimycin A. Mitochondrial complex III inhibitor; indirect ROS/GSK3-associated c-Myc destabilization, not demonstrated c-Myc binding.	E-H1, HCT116, HeLa, MIA PaCa-2, A549, PANC-1, HL-60; accelerated turnover. No animal efficacy or in vivo degradation kinetics.	CHX, Ub, stable mRNA, GSK3 controls and T58A support the route. Ub trapping with MG132 is not a separate rescue assay; remaining validation needs include E3 genetics and ATP/translation controls.	An indirect stress signal does not require nuclear drug delivery. Safe systemic c-Myc-active exposure has not been established.	Mitochondrial toxicity limits specificity; potential metabolic/antioxidant compensation. Manufacturing considerations: natural-product congeners/composition. The therapeutic window remains unresolved.	Peer-reviewed cellular mechanistic study; research tool rather than mature c-Myc therapy [54].
III. Adaptable or proposed platforms without demonstrated direct c-Myc degradation
TKD (tumor-targeting KRAS degrader) → c-Myc. Proposed adaptation of BR2–KRAS nanobody–CMA motif. Kd ≈ 6.57 nM concerns KRAS, not c-Myc.	Original TKD: HCT116, H358, HT29/FHC; subcutaneous and orthotopic HCT116-luc models. No c-Myc-specific DC50/Dmax or degradation kinetics.	KRAS lysosomal rescue/motif controls do not validate c-Myc degradation. New c-Myc binder, c-Myc-loss/synthesis controls and LAMP2A/HSPA8 validation required.	c-Myc retargeting requires verified cellular/nuclear-pool access and productive lysosomal routing. Original TKD PK cannot be transferred to a new construct.	c-Myc selectivity unestablished; potential binder/CMA/delivery liabilities. Recombinant modular manufacture is plausible, but retargeting requires new quality/activity validation.	Peer-reviewed KRAS preclinical platform; direct c-Myc degradation remains hypothetical. Downstream RAS effects are not target-degradation evidence [59].
MNT–CMY-CVH-12-321. Receptor-targeted recombinant nanobody transporter; no validated c-Myc-proteolytic module. EGFP-c-Myc Kd = 46 ± 14 nM.	A431: receptor-dependent internalization and reduced nucleolin protein abundance. MCF7: MTT-based proliferative activity approximately 81 ± 5% of the control MNT condition after 500 nM treatment for six days. No direct c-Myc-loss kinetics or animal validation.	Remaining validation needs: direct c-Myc-loss measurements, synthesis controls and pathway-specific rescue/genetics. UPS adaptation needs E3 dependence/c-Myc-Ub; uptake and nucleolin are not degradation endpoints.	NLS and pH-liposome activity do not prove functional nuclear delivery. Systemic and nuclear active-construct exposure remain unestablished.	Potential receptor/escape/epitope and future-pathway liabilities; degradation selectivity unproven. Manufacturing considerations: multidomain folding, endotoxin and each module’s activity.	Peer-reviewed binding/delivery and functional study; proposed degradation extension only, without clinical evidence [70].

Abbreviations: AML, acute myeloid leukemia; ATP, adenosine triphosphate; BLI, biolayer interferometry; CHIP, C-terminus of Hsc70-interacting protein; CHX, cycloheximide; CMA, chaperone-mediated autophagy; CPP, cell-penetrating peptide; CRBN, cereblon; cryo-EM, cryo-electron microscopy; DC₅₀, concentration producing a 50% reduction in target protein abundance relative to the control at a specified time point; DHA, dihydroartemisinin; D_max, maximum observed reduction in target protein abundance under the specified assay conditions; DUB, deubiquitinase; E1, ubiquitin-activating enzyme; E3, ubiquitin ligase; EGFP, enhanced green fluorescent protein; Fbw7, F-box/WD repeat-containing protein 7 (encoded by FBXW7); GMP, good manufacturing practice; GSK3, glycogen synthase kinase 3; GSPT1, translation termination factor eRF3a; HPLC, high-performance liquid chromatography; Hsp70, heat shock protein 70; HSPA8, heat shock protein family A member 8 (Hsc70); IC₅₀, half-maximal inhibitory concentration; ISR, integrated stress response; IV, intravenous; K_d, equilibrium dissociation constant; KO, knockout; LAMP2A, lysosome-associated membrane protein 2A; LGMN, legumain; MAX, Myc-associated factor X; MIDN, midnolin; MNT, modular nanotransporter; MS, mass spectrometry; NLS, nuclear localization signal; PD, pharmacodynamics; PD-L1, programmed death-ligand 1; PDX, patient-derived xenograft; PEI, polyethylenimine; PK, pharmacokinetics; PR, partial response; PROTAC, proteolysis-targeting chimera; rLon, recombinant Lon protease; ROMP, ring-opening metathesis polymerization; ROS, reactive oxygen species; SD, stable disease; SI, supplementary information; SPR, surface plasmon resonance; tMyc, N-terminally truncated c-Myc; TNA, threose nucleic acid; Ub, ubiquitin; UPS, ubiquitin–proteasome system; USP28, ubiquitin-specific peptidase 28; VHL, von Hippel–Lindau tumor suppressor. Model designations: NOD-SCID, non-obese diabetic/severe combined immunodeficient mice; NSG, NOD scid gamma mice. “Remaining validation needs” denotes priorities for further verification, not necessarily the complete absence of experiments of that type. The table entries emphasize platform-specific gaps; general synthesis controls are not repeated in every row. The platforms selected for comparison illustrate mechanistic diversity and are not intended to constitute an exhaustive catalogue. Cross-platform comparisons should distinguish mechanistic confidence from translational maturity. Evidence for target recruitment and pathway dependence is more developed for some constructs, whereas delivery, active-agent exposure, or separation of protein turnover from synthesis remains limiting for others. Reported DC₅₀ values cannot support a simple potency ranking because reporter design, formulation, exposure duration, and cellular context differ. Local antitumor activity also does not establish systemic pharmacology or a clinically usable therapeutic window.

8. Resistance Mechanisms, Pharmacokinetic Barriers, On-Target Toxicity, and Therapeutic Window of TPD Therapy

8.1. Modality-Specific Mechanisms of Drug Resistance and Pharmacokinetic Exposure Barriers

Resistance to c-Myc-directed degradation may arise through modality-specific changes in target engagement, degradation-pathway competence, or exposure. Altered c-Myc binding sites or epitope accessibility are candidate mechanisms that require direct testing for each construct. Resistance mechanisms identified in other CRBN-dependent therapies and degrader systems provide additional hypotheses. In multiple myeloma, hypermethylation of an intronic CRBN enhancer has been associated with reduced CRBN expression and resistance to immunomodulatory drugs; the examined promoter remained unmethylated [71]. Experimental loss of CUL4B conferred lenalidomide resistance, whereas the tested CUL4B missense variants did not reproduce this effect [72]. Genetic perturbation studies of other targeted degraders have implicated UBE2M-dependent neddylation and CRL regulatory factors, including the COP9 signalosome and CAND1, in drug sensitivity [73]. These findings do not establish the same resistance mechanisms for c-Myc-directed degraders. For GT19630, reduced CRBN expression was reported in resistant HL-60 cells, and CRBN knockout protected cells from treatment-induced death [37]. Strategies that warrant evaluation include recruitment of alternative E3 ligase machinery, as exemplified by VHL- and CHIP-based c-Myc-directed approaches [18,43]; Keap1-recruiting designs have also been evaluated within the c-Myc-directed HYDRAC platform [17], while Keap1 recruitment in MNTs has been demonstrated for a different target [68]. Ubiquitin-independent MIDN-recruiting chimeras [44] and the orthogonal bacterial protease rLon [46,47] provide mechanistically distinct approaches, but their ability to overcome resistance to a particular c-Myc degrader requires direct testing.

Classical PROTACs often have relatively high molecular weight, substantial polar surface area, and conformational flexibility [20,22,23], which may limit membrane permeability and contribute to metabolic liabilities, including oxidation of susceptible polyethylene glycol linkers [23]. PROTAC optimization can include linker rigidification and reduction in molecular size or polarity [23]. Molecular glue development offers a distinct design strategy [22]. Degrader–antibody conjugates (DACs) use antibodies against internalizing cell-surface antigens, such as HER2, to promote selective cellular uptake. Following intracellular processing and payload release, the active degrader must reach the cytosol and, where required, the nucleus to engage its intracellular target; the release mechanism depends on the conjugate and linker design [26,74]. In contrast, LYTACs bridge extracellular or membrane-associated target proteins to cell-surface lysosome-shuttling receptors, such as CI-M6PR, promoting target internalization and lysosomal degradation without requiring delivery of an active small-molecule degrader to the cytosol [26,75,76,77]. Anti-drug antibodies (ADAs) are a potential source of altered exposure or reduced activity for protein-based constructs; their incidence and functional effects require construct-specific assessment, as discussed in Section 8.4. Compensatory activation of signaling pathways, including AKT and ERK1/2, may contribute to resistance in some settings [5,40]. Such findings provide a rationale for testing mechanism-informed combinations with pathway inhibitors or immunotherapy [28,40,75,78]. The durability of c-Myc depletion depends on the balance between induced turnover and ongoing protein synthesis. Recovery after washout may reflect target resynthesis, loss of intracellular active agent, or both, and should not by itself be interpreted as acquired resistance. Time-resolved measurements of target abundance, nascent synthesis, and active-agent exposure are therefore needed to distinguish these possibilities; polymer retention is a particular consideration for HYDRACs [17].

Additional candidate resistance mechanisms include changes in c-Myc/MAX association or epitope accessibility, adaptation of proteasomal processing, and impaired endosomal escape or nuclear delivery. For MIDN- and CMA-dependent approaches, the availability and function of MIDN, HSPA8, LAMP2A, and the relevant proteolytic machinery warrant investigation. The pathway dependencies described in the reviewed studies provide a rationale for testing these possibilities, rather than evidence of acquired resistance to a specific c-Myc-directed construct [44,45]. Intratumoral heterogeneity in receptor expression, delivery, and pathway competence may also produce uneven target depletion and should be examined alongside population-average responses.

8.2. Physiological Barriers and On-Target Toxicity of Systemic c-Myc Elimination

c-Myc regulates ribosome biogenesis, metabolism, cell-cycle progression, and nucleotide synthesis [15,79,80], and contributes to the maintenance and regeneration of several healthy tissues [81,82,83]. These physiological functions raise concerns about on-target toxicity, particularly in proliferating intestinal, hematopoietic, and immune-cell populations. Genetic MYC deletion, pharmacological inhibition, and targeted degradation differ in their effects on target abundance, function, and recovery. Their safety therefore requires modality-specific assessment of tissue and developmental context, exposure, depth and duration of c-Myc suppression, and dosing schedule. In the intestinal epithelium, c-Myc participates in Wnt/β-catenin/TCF-4-dependent regulation of crypt progenitor cells [82,83]. Context-dependent effects on crypt proliferation and maintenance in genetic studies identify intestinal integrity and recovery as priorities for degrader safety assessment [82,83].

In hematopoietic tissues, c-Myc contributes to the balance between stem-cell self-renewal and differentiation [81,84]. Embryonic and conditional deletion studies establish these physiological roles [8,84,85,86]; their relevance to degrader safety follows the modality-specific assessment outlined above. Altered adhesion and retention of hematopoietic stem cells within their niches have been described in genetic models [84]. The extent to which a particular c-Myc degrader affects mature blood-cell production therefore requires direct assessment of its exposure, target depletion, dosing schedule, and effects on normal progenitors. MYC-dependent metabolic reprogramming contributes to lymphocyte activation, as demonstrated by conditional c-Myc deletion in primary T cells [87]. Effects on lymphocyte proliferation, viability, and function should be assessed at the exposures achieved by each degrader.

8.3. Therapeutic Window and the Concept of “Myc Addiction”: Molecular Basis of Selectivity

Functional dependence on c-Myc may provide a basis for differential responses between tumors and normal tissues [15,79]. Increased MYC expression and altered transcriptional programs can contribute to tumor maintenance, but high c-Myc abundance alone does not establish oncogene addiction or predict sensitivity to a degrader. The consequences of c-Myc suppression also depend on the cellular context, including checkpoint function, compensatory pathways, and the extent and duration of target modulation [15,79]. In specific mouse models using reversible Omomyc expression, tumor regression occurred alongside effects on proliferating normal tissues that were reversible after Omomyc withdrawal [10]. Together with early Phase I clinical experience with the c-Myc inhibitor OMO-103 [88], these findings support further investigation of a therapeutic window. Applying the modality-specific principle outlined in Section 8.2, degrader studies should quantify normal-tissue effects and recovery in relation to exposure and target depletion.

8.4. Engineering Strategies to Expand the Therapeutic Window: Targeted Delivery, E3 Ligase Profiling, and Deimmunization

Targeted delivery strategies aim to improve the distribution of degraders and reduce unwanted exposure in normal tissues [26,78]. DACs directed against internalizing tumor-associated antigens, such as HER2, can facilitate selective uptake and intracellular payload release [26,74]. The effects of antigen, linker, payload, and dosing regimen on systemic and tissue exposure should be related to bone-marrow and intestinal tolerability. LYTACs instead direct accessible extracellular or membrane-associated targets to lysosomes through receptors such as CI-M6PR/IGF2R [26,75,76,77]. Their relevance to c-Myc-associated signaling depends on the selected surface or extracellular target. Nanobody-based formats may offer useful delivery properties, but tumor penetration, normal-tissue accumulation, and clearance require construct-specific assessment [89,90]. Differences in the abundance and activity of the recruited E3 ligase machinery may contribute to cellular selectivity [91]. For CRBN-, VHL-, and Keap1-recruiting constructs, tumor and normal hematopoietic cells should be compared for ligase activity, MYC dependence, intracellular exposure, degradation capacity, and viability to establish whether recruitment confers a therapeutic advantage.

For protein-based degraders, repeated-dose studies should assess binding ADAs and, where detected, characterize their neutralizing activity and potential effects on pharmacokinetics, pharmacodynamics, and tolerability. Cytokine changes and infusion reactions should be evaluated separately, as they do not by themselves demonstrate ADA-mediated neutralization. Relevant clinical precedents include separate ADA and neutralizing-antibody measurements for ozoralizumab [92] and ADA monitoring in the Phase I OMO-103 study [88]; neither study establishes the immunogenicity profile of a c-Myc degrader. Studies of rLon have evaluated intravesical delivery in mouse bladder cancer models and oral delivery in mouse colon cancer models [46]. Evaluation of systemic rLon requires route- and construct-specific pharmacokinetic, immunogenicity, and toxicology studies.

For VHH-based constructs, humanization and framework engineering may reduce immunogenicity risk [89], but do not guarantee its elimination, as illustrated by ADAs detected against humanized ozoralizumab [92]. Optimization should include experimental assessment of immunogenicity and preservation of stability, c-Myc-binding affinity, and biological activity, with affinity values reported for the specific engineered construct and assay.

8.5. Candidate Biomarkers and Validation Requirements for Prospective Patient Stratification

Prospective studies should distinguish candidate predictors of treatment response from pharmacodynamic measures of MYC inhibition and assessments of exposure, safety, and immunogenicity. Each candidate requires validation for the specific therapeutic platform and disease context. MYC amplification, translocations, and c-Myc protein abundance should be evaluated alongside functional MYC dependence rather than treated as interchangeable measures. The WBC100 study provides preclinical evidence relating c-Myc abundance to compound sensitivity [32], whereas neither MYC amplification nor overexpression was an inclusion criterion in the Phase I OMO-103 trial [88]. In that trial, changes in MYC transcriptional signatures in paired biopsies supported pharmacodynamic assessment; these findings concern a c-Myc inhibitor and do not validate biomarkers for degraders [88]. The status of p53, p21, and p16^INK4a may be considered as exploratory biological covariates, but is not established as a predictive panel for c-Myc degrader therapy. Experimental analyses of MYC promoter occupancy at different c-Myc concentrations provide a mechanistic basis for investigating lower-affinity regulatory sites [93]; their use in patient selection would require assay standardization and prospective clinical validation.

For ubiquitin-dependent platforms, candidate biomarkers of degradation-pathway competence should be matched to the recruited machinery. For GT19630, CRBN knockout and studies of resistant HL-60 cells support investigation of CRBN expression and function [37]. For WBC100, CHIP knockdown supports investigation of CHIP-dependent activity [32]. VHL recruitment in the deoxyoligonucleotide PROTAC study provides a rationale for assessing VHL-pathway competence, but does not establish a predictive expression threshold [43]. CRBN enhancer methylation, CUL4B loss, and perturbation of neddylation or CRL regulation are supported by studies of other therapies and remain exploratory candidates for c-Myc-directed platforms [71,72,73]. FBXW7-mediated c-Myc turnover [25] and the TRIB3–UBE3B pathway [27] provide mechanistic grounds for candidate assessments only where the intervention depends on those endogenous pathways. These factors are not interchangeable predictors, and their clinical predictive value requires platform-specific validation.

For antibody-mediated delivery platforms, candidate delivery determinants include surface-antigen abundance, internalization, and productive intracellular payload release. The HER2-directed DACs study provides a primary example of receptor-associated selective delivery, but its payload targeted RIPK2 rather than c-Myc [74]. For LYTACs, accessible extracellular or membrane-associated targets and the recruited lysosome-shuttling receptor, such as CI-M6PR/IGF2R, are mechanistically relevant [77]; these features do not establish response biomarkers for intracellular c-Myc degradation. Serial measurements of AKT and ERK1/2 phosphorylation could be explored as pharmacodynamic readouts of adaptive signaling. Their ability to predict response or guide combination treatment remains to be demonstrated for each c-Myc-directed platform.

For protein- and nanobody-based constructs, binding ADAs, neutralizing activity, and associated changes in drug exposure should be evaluated as immunogenicity and pharmacokinetic endpoints, rather than as markers of tumor c-Myc dependence. Construct-specific immunogenicity assessment is discussed in Section 8.4. Circulating cytokines and selected immune-cell populations may support exploratory pharmacodynamic or safety analyses. The soluble-factor signatures reported for OMO-103 require further validation and cannot be transferred directly to degrader-based treatment [88]. Immune measurements should distinguish tumor-associated immune changes from unwanted suppression of activated immune cells and from inflammatory responses to the administered construct. Together, these assessments define a research framework; predictive value, assay performance, sampling schedules, and treatment-decision thresholds require prospective validation.

9. Promising Directions, Research Priorities, and Combination Strategies

9.1. Synergy with Immuno-Oncology and Microenvironment Remodeling

MYC suppression can alter tumor–immune interactions. In mouse tumors and human tumor cells, c-Myc bound to the promoters of CD47 and CD274 (PD-L1), and MYC suppression reduced their expression; enforced expression of these immune regulators limited immune-mediated tumor regression in the investigated models [94]. These findings provide a rationale for testing combinations of c-Myc-directed degraders with immune checkpoint inhibitors, but do not establish that each degrader reproduces these effects or converts an immunologically “cold” tumor into an immunotherapy-responsive one. Therapeutic synergy requires direct testing in immunocompetent models. Such studies should distinguish tumor-intrinsic checkpoint modulation from effects on normal immune cells, including c-Myc-dependent metabolic responses in activated T cells [87], and from nonspecific inflammation induced by delivery carriers or exogenous proteins.

9.2. Nanotechnology-Based Delivery and Independent Biological Degradation Platforms

To overcome the pharmacokinetic barriers of PROTACs and macromolecular degraders, targeted delivery platforms are being actively developed; however, delivery vehicles must be evaluated as an integral part of the active drug product rather than as a generic solution to all degrader limitations [31]:

• Nanoparticles, polymeric carriers, and nucleic acid formulations: Encapsulation of degraders into lipid nanoparticles, complexation with polyethyleneimine (PEI), circularization of aptamers, or conjugation with selenium nanoparticles may improve specific delivery steps—such as enzymatic stability or cellular uptake—but their benefits, liabilities, and levels of evidence depend strictly on the specific payload and route of administration [31,42,43,45,95]. Specifically, local peritumoral administration of circular circPA1-ProMyc [42], intravenous administration of PEI-formulated MP-16/MP-17 [43], and strictly cellular (in vitro) evaluations of the nano-selenium conjugate Se-MYC-LYSO [45] represent fundamentally different levels of delivery validation.
• Degrader–Antibody Conjugates (DACs): These conjugates combine the high receptor selectivity of monoclonal antibodies with the degradative activity of PROTAC [21]. Nevertheless, effective c-Myc targeting via DACs requires validated receptor-dependent internalization and productive cytosolic release of an active degrader [21,31].
• Amorphous calcium phosphate nanoplatform for antibody/TRIM21 co-delivery: This system enables the cytosolic co-delivery of antibodies and the TRIM21 E3 ubiquitin ligase, supporting intracellular delivery and UPS-mediated c-Myc degradation, cell cycle arrest, and apoptosis in the mammalian cell and mouse models examined [96]. This system is discussed here as an example of antibody/E3 ligase co-delivery, outside the selected mechanistic comparison in Table 3.

9.3. Computational Design, Artificial Intelligence, and Experimental Validation

Structure-based and AI-assisted design can support the development of peptide-based c-Myc degraders, as illustrated by the approaches discussed above [44,45]. Computational predictions cannot by themselves establish target degradation, nuclear delivery, proteome selectivity, or safety. A prospective workflow could use computational models to prioritize candidates for synthesis and initial biochemical and cellular testing, followed by evaluation in patient-derived organoids to assess activity in more complex tumor models. Meaningful cross-platform comparisons would require matched intracellular exposure and quantitative target-loss endpoints.

10. Conclusions

Targeted c-Myc degradation is supported by biochemical and preclinical evidence across small-molecule, oligonucleotide, polymeric, and protein-based approaches, although mechanistic validation varies among platforms [17,18,19,32,37,41,42,43,44,45,46,47]. Indirect agents can accelerate endogenous turnover or reduce MYC expression, whereas c-Myc-directed adaptations of TKD and degradation-enabled MNTs remain proposed strategies [52,53,54,55,56,57,58,59,70]. Preliminary Phase I observations for WBC100 provide an early clinical signal, but clinical efficacy of c-Myc degradation remains unestablished [33].

Comparison and translation are limited by differences in assay systems, exposure, delivery methods, and the completeness of degradation evidence. Selectivity of delivery of an agent targeting c-Myc into cancer cells, its target binding, reduction in protein abundance, and antitumor activity each require distinct experimental support. Active fragments, concurrent effects on translation, and reporter-dependent measurements complicate interpretation [19,37,44]. Further barriers include productive intracellular delivery, active-agent pharmacokinetics, proteome selectivity, resistance, manufacturing reproducibility, and tolerability in normal tissues; local animal efficacy provides limited information about systemic treatment [17,42,43,46,47].

Priority studies should apply mechanism-appropriate validation of target loss and pathway dependence while separating degradation from reduced synthesis. Comparisons should report exposure, time-dependent degradation, and recovery alongside functional outcomes. Development should then link active-agent PK/PD to tumor and normal-tissue responses, investigate resistance and immunogenicity where relevant, and establish reproducible manufacturing. Proposed platforms require direct c-Myc-degradation evidence, while combination strategies require testing in models that capture both tumor and host immune effects. These steps will help identify approaches with a measurable therapeutic window and a credible basis for clinical evaluation [5,31,44,45,75,87,94]. Future studies should also prioritize tumor-cell-selective delivery of c-Myc degraders to limit exposure of normal cells and reduce potential adverse effects.