Search Results (445)

Epigenetic dysregulation is a defining feature of solid tumors. Among epigenetic regulators, the nuclear receptor-binding SET domain (NSD) family of histone methyltransferases, comprising NSD1, NSD2, and NSD3, have emerged as critical mediators of oncogenic chromatin remodeling and transcriptional regulation. These enzymes primarily catalyze histone H3 lysine 36 (H3K36) methylation, thereby regulating chromatin accessibility, transcriptional programs, DNA damage repair, and genome stability. Aberrant expression, mutation, amplification, and chromosomal rearrangement of NSD family members have been identified across tumors, establishing them as key epigenetic drivers of malignancy. Accumulating evidence demonstrates that NSD proteins promote multiple hallmarks of cancer, including sustained proliferative signaling, invasion and metastasis, immune evasion, metabolic reprogramming, genome instability, and therapeutic resistance. Although NSD proteins share overlapping catalytic functions, each exhibit distinct biological roles and mechanisms of dysregulation in solid tumors. Advances in structural biology, medicinal chemistry, and targeted protein degradation have accelerated the development of selective NSD inhibitors, chromatin-reader antagonists, and proteolysis-targeting chimeras (PROTACs), establishing the feasibility of pharmacologically targeting NSD-dependent epigenetic pathways. In this review, we summarize the biological functions of the NSD family, discuss their oncogenic mechanisms in solid tumors, and highlight recent progress in therapeutic targeting. Full article

Matrix metalloproteinases (MMPs) have long been recognized as key mediators of tumor invasion and metastasis due to their capacity to degrade extracellular matrix components. However, clinical failure of broad-spectrum MMP inhibitors has revealed a more complex and context-dependent role for these proteases in cancer. Among them, macrophage metalloelastase, MMP-12, has emerged as a particularly intriguing enzyme with both tumor-promoting and tumor-suppressive functions. Predominantly expressed by tumor-associated macrophages, MMP-12 occupies a unique position at the interface of proteolysis, inflammation, and immune regulation within the tumor microenvironment. Accumulating evidence from experimental models and clinical studies demonstrates that MMP-12 can exert potent anti-tumorigenic effects, primarily through inhibition of angiogenesis. Mechanistically, MMP-12 generates angiostatin and other anti-angiogenic fragments, suppresses vascular endothelial growth factor signaling, and reduces tumor vascularization, thereby limiting tumor growth and metastatic expansion. In several cancer types, including lung, colorectal, and hepatocellular carcinoma, elevated MMP-12 expression has been associated with reduced tumor progression and improved patient outcomes. Conversely, MMP-12 can also promote tumor progression through extracellular matrix remodeling, facilitation of invasion, and modulation of inflammatory pathways, particularly in environments characterized by chronic inflammation or immunosuppressive macrophage phenotypes. These seemingly contradictory roles are governed by multiple context-dependent factors, including macrophage polarization, tumor type, disease stage, and microenvironmental cues such as hypoxia and cytokine signaling. In this review, we comprehensively examine the molecular regulation, functional mechanisms, and clinical relevance of MMP-12 in cancer. We highlight the dualistic nature of MMP-12 activity and discuss its implications for therapeutic strategies, emphasizing the need for selective and context-aware targeting approaches rather than broad inhibition of MMP activity. Full article

Age-related skeletal muscle wasting, clinically expressed as sarcopenia and frailty, significantly limits the efficacy of physical rehabilitation due to an underlying cellular bioenergetic decline, mitochondrial dysfunction, and chronic inflammaging. This narrative review synthesizes current physiological and clinical evidence evaluating mitochondria- targeted nutraceuticals as targeted metabolic adjuvants to physical exercise in older adults. Comprehensive literature searches were executed across PubMed, Web of Science, and Scopus following SANRA guidelines and the SPIDER framework to evaluate functional and bioenergetic outcomes in geriatric cohorts. The findings demonstrate that target-specific biofactors directly impact mitochondrial restrictions: ubiquinol and NAD⁺ precursors restore electron transport chain efficiency and biogenesis; urolithin A upregulates mitophagy to prevent the cytosolic extrusion of pro-inflammatory mitochondrial DNA, while creatine monohydrate and omega-3 polyunsaturated fatty acids selectively restore downstream myofibrillar anabolic pathways. When translated to specialized clinical settings, including post-fracture orthopedic immobilization, chronic pain syndromes managed, and post-ICU-acquired weakness, these bioenergetic substrates safely mitigate tissue proteolysis and enhance recovery kinetics. In conclusion, structurally integrating biomarker-driven nutritional rehabilitation pathways with tailored exercise protocols provides the precise pro-anabolic microenvironment necessary to overcome anabolic resistance, ultimately shortening recovery timelines and maximizing functional independence in the aging population. Full article

Targeted protein degradation (TPD) represents a whole new paradigm in cell-level therapeutic design, with its ability to remove target proteins, normally through the endogenous proteasomal, lysosomal, or autophagic systems, rather than the traditional occupancy-driven inhibition approach. But the clinical efficacy of degraders is becoming more restricted based on delivery rather than efficacy only. Many proteolysis-targeting chimeras and new proximity-inducing systems have low solubility, are impermeable, are pharmacodynamically complicated, lack tissue selectivity, and cannot fully access the intracellular space. Nanomedicine and PD platforms could provide strategies not only to overcome these challenges, but also to provide other advantages, including enhancing exposure to degraders, biodistribution, controlled release, and context-dependent activation. This critical review is an outline of all lipid, polymeric, inorganic, biomimetic, targeted, activatable, and self-assembling delivery systems for TPD. We assess compositional considerations, in vitro and in vivo evidence, challenges for translation, and clinical endpoints required to support delivery-enabled degradation. Trusted TPD therapeutics need to relate different aspects of their design, such as degrader chemistry, carrier structure, disease biology, and pharmacodynamic biomarkers, to one another. Further investigations are needed to establish intact delivery of the degrader to the target, target depletion in relevant tissues, prolonged pharmacodynamics, favorable safety, and compelling therapeutic benefit relative to free degraders or traditional inhibitors. Thus, it is important to view delivery not simply as an additional step during formulation but as a design principle necessary for the reliable clinical outcome of degradation medicine. Full article

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules that induce the selective degradation of a protein of interest by recruiting an E3 ubiquitin ligase, thereby triggering ubiquitination and proteasomal clearance. As part of the broader targeted protein degradation (TPD) paradigm, PROTACs offer a powerful strategy to eliminate pathogenic proteins that are difficult to modulate with traditional occupancy-based inhibitors. However, their clinical translation is often limited by poor aqueous solubility, suboptimal cellular permeability, and off-target effects. Notably, some PROTACs retain potent biological activity despite limited membrane permeability, owing to their catalytic mechanism of action, which allows even a small number of molecules reaching the target site to drive substantial protein degradation and produce important pharmacological effects. Growing evidence supports the application of PROTAC-based approaches in neurodegenerative diseases, where the selective removal of toxic or misfolded proteins is particularly attractive. This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development. Full article

Colorectal cancer is a leading cause of cancer death, yet its molecular heterogeneity remains poorly translated into individualized treatment. We present a reproducible artificial intelligence (AI) framework that integrates multi-omics benchmarking, sample-level drug prioritization, E3 ubiquitin ligase selection, and shape-anchored Proteolysis Targeting Chimera (PROTAC) design for KRASG12D in colon adenocarcinoma (COAD). A controlled synthetic benchmark comprising 425 tumor and 41 simulated normal profiles, parameterized to match The Cancer Genome Atlas (TCGA) distributions, was used for pipeline verification. Among sixteen methods, the Balanced Latent Integration with Stability Selection (BLISS) model achieved the highest silhouette width (0.86) and competitive agreement (Adjusted Rand Index, ARI, 0.90). The pipeline was validated on real data: a TCGA COAD cohort (186 tumors) with independent Consensus Molecular Subtype (CMS) labels and a CPTAC cohort (104 tumors). Integration modestly recovered CMS (ARI 0.28), and stage, not molecular cluster, drove survival (log-rank p = 0.005 versus 0.81). Sample-level prioritization differed from cluster-level ranking in 82.6% of profiles, below chance (p < 0.0001), without indicating efficacy. Candidate NOVEL00489 showed a good MM-GBSA estimate, matching the reference ASP3082. Compounds are computational candidates requiring experimental validation. This establishes a transparent benchmark for in silico degrader generation in precision oncology. Full article

Proteases are widely studied hydrolases as “green technologies” for degrading structures within complex matrices, although combining different classes poses challenges for catalytic stability. To the best of our knowledge, this is the first study to specifically evaluate the biochemical control of Cryptosporidium spp. oocysts using plant- and microbial-derived proteases. This study evaluated the compatibility and sanitizing potential of the microbial serine protease subtilisin Carlsberg (HPF-1SCA) and the plant cysteine protease papain (1PPP), both individually and in a 15% (w/v) combination, hypothesizing a synergistic effect due to their distinct catalytic specificities, as a potential biochemical approach to reduce contamination by these zoonotic protozoa of global importance, which are highly resilient to conventional disinfectants. The experimental design comprised five distinct treatment groups: a negative control (distilled water), a positive chemical control (0.04% v/v NaClO), treatment with isolated papain (15% w/v), treatment with isolated microbial HPF formulation (15% w/v), and a combined treatment using both enzymes simultaneously (15% w/v each). Concurrently, an in silico molecular docking investigation was conducted to elucidate the predicted binding scores, structural compatibility, and preferential binding mechanisms of these enzymes toward the Cryptosporidium Oocyst Wall Protein (COWP). In vitro compatibility assays revealed an immediate antagonistic effect due to mutual proteolysis, reducing overall proteolytic activity by 45% after 72 h. Despite this antagonism, the enzyme mixture (G5) and the isolated microbial protease (G4) achieved a 93% reduction in oocysts, equivalent to the conventional 0.04% NaClO treatment (G2), while papain (G3) achieved 65%. All these results represented statistically significant efficacy (p < 0.01) compared to the negative control (G1). In silico molecular docking studies provided a structural predictive basis for the experimental data, suggesting that subtilisin Carlsberg (HPF-1SCA) exhibits more favorable predicted binding scores and structurally compatible interfaces, compared to papain, particularly toward the major oocyst structural proteins COWP8 (estimated ΔG = −15.2 kcal·mol⁻¹) and COWP6 (estimated ΔG = −13.3 kcal·mol⁻¹). This provides robust evidence for initial target recognition and molecular anchoring, although these static models do not definitively confirm catalytically productive cleavage conformations. In summary, this in vitro proof-of-concept demonstrates that microbial proteases show promise for the biochemical destabilization of oocysts without generating toxic chlorinated byproducts. While these baseline findings align with the One Health concept, future field-scale validations assessing enzyme stability under variable environmental conditions and in vivo infectivity assays are required before practical application in sanitation protocols. Full article

Insect protein farming offers sustainable advantages in land efficiency, emission reductions, and bioconversion, yet optimizing the nutrient composition remains a major challenge for cost-effective production. This study investigates the co-regulatory mechanism between alkali-soluble protein (SpA) and the gut microbiota in black soldier fly larvae (Hermetia illucens) and their effect on protein conversion efficiency. Feeding trials with varying alfalfa/SpA ratios identified a wheat middlings/alfalfa meal blend at a (5:0 ratio) as optimal for promoting larval protein accumulation. SDS-PAGE and 16S rRNA analyses revealed a strong positive correlation between SpA and larval crude protein (R² = 0.82). The network analysis and Pearson correlation heatmap further confirmed positive correlations among SpA, larval protein, Enterococcus, and Ignatzschineria (p < 0.05), suggesting that high SpA in the substrate was associated with the enrichment of these taxa, which synergistically enhanced proteolysis through alkaline protease secretion (R² = 0.85) and chitinase-mediated gut remodeling. Multi-linear regression modeling verified SpA as a superior predictor of the crude protein content compared with total nitrogen (TN), improving the model’s coefficient of determination (R²) from 0.40 to 0.82. These findings highlight SpA’s higher bioavailability and its direct role in metabolic utilization. By integrating the feed composition, microbiome function, and host metabolism, this study established a regulatory network driving larval protein biosynthesis. The targeted modulation of dietary SpA content may offer a promising approach to enhance beneficial microbial communities and improve protein conversion efficiency in BSFL-rearing systems. These findings provide a theoretical basis for optimizing feed formulations to support sustainable insect protein production from organic waste. Full article

Background: Sarcopenia, the age-related loss of muscle mass and strength, affects over 20% of older adults in Taiwan and contributes to frailty and functional decline. Nutritional supplementation offers a promising strategy for those unable to engage in structured exercise, yet multi-ingredient MCT–leucine–creatine-based interventions remain understudied in clinically defined sarcopenic populations. Methods: We conducted an 8-week randomized, double-blind, placebo-controlled trial at National Taiwan University Hospital (ClinicalTrials.gov NCT06376266). Seventy-three older adults (mean age 77.3 ± 7.7 years) meeting AWGS 2019 sarcopenia criteria were randomized to TLN-01 (a multi-ingredient supplement containing whey protein, branched-chain amino acids, medium-chain triglycerides, creatine, resveratrol, and vitamin D₃, n = 34) or isocaloric placebo (n = 39). Primary outcomes were changes in appendicular skeletal muscle mass (ASM) assessed by DXA and handgrip strength. Targeted plasma amino acid metabolomics (LC-MS) was performed as an exploratory endpoint. Results: ASM increased significantly in the TLN-01 group (+0.42 kg, +3.2%; p < 0.001) but remained unchanged in controls (p = 0.785), with a significant between-group difference (ANCOVA p < 0.01); this absolute change was below the commonly cited minimal clinically important difference. Handgrip strength did not differ significantly between groups (p = 0.32); within-group analysis showed a significant decline in the placebo group (−7.0%; p < 0.001) that was not observed in the intervention group (p = 0.537). Metabolomic analysis revealed reductions in plasma taurine and 1-methylhistidine and an increase in kynurenine; given the absence of clear separation on PCA/PLS-DA, these findings are considered exploratory and hypothesis-generating rather than confirmatory evidence of altered amino acid utilization or proteolysis. No clinically significant adverse metabolic or renal events occurred. Conclusions: Eight weeks of this multi-ingredient MCT–leucine–creatine-based supplement induced a modest increase in muscle mass and attenuated the decline in handgrip strength observed in the placebo group among sarcopenic older adults without a structured exercise program, supporting further investigation as a safe and practical nutritional adjunct in geriatric care. Full article

KMT2A-rearranged (MLL-r) leukemias are highly aggressive hematological malignancies that require improved targeted therapies. DOT1L (histone H3K79 methyltransferase) functions as a critical oncogenic driver and represents an important therapeutic target in these high-risk leukemias. However, clinical responses to the first-in-class DOT1L inhibitor pinometostat (EPZ5676) have been modest, attributed to suboptimal pharmacokinetics and, more fundamentally, to the recognition that DOT1L possesses methyltransferase-independent functions that evade catalytic inhibition. This highlights the need for strategies that abrogate the full spectrum of DOT1L activity to effectively treat these high-risk leukemias. Proteolysis-targeting chimeras (PROTACs), which induce selective degradation of the DOT1L protein rather than inhibiting its catalytic activity, have therefore emerged as a promising approach. Notably, VHL-recruiting DOT1L PROTACs, such as DOT1L808, have demonstrated improved pharmacokinetic profiles and potent antileukemic activity in preclinical in vivo models. However, these findings remain preclinical, and significant challenges including oral bioavailability, potential toxicity, and lack of clinical validation must be addressed before clinical translation. In this review, we provide an overview of the evolving understanding of the biology of DOT1L, discuss existing MLL small molecule therapies, and evaluate current advances in therapeutically targeting DOT1L, with particular focus on the targeted degradation of DOT1L as a promising therapeutic strategy for high-risk KMT2A-r leukemia. Full article

Kinases are highly explored drug targets due to their central role in cell growth, differentiation, and cell death, as well as their relationship to cancer initiation and progression. However, with more than 500 kinases in the human kinome and significant structural similarities among them, kinases present a major selectivity challenge. Bruton’s tyrosine kinase (BTK), a highly studied kinase, plays an important role in the B-cell receptor pathway. Overexpression of BTK in B cells has been linked to the development of B-cell lymphomas, like chronic lymphocytic leukemia (CLL), as well as certain autoimmune diseases. For this reason, BTK is an attractive therapeutic target. In this review, we will provide a summary of the design of irreversible inhibitors, reversible inhibitors, and Proteolysis-targeting chimera (PROTAC) degraders targeting BTK. We will include crystal structures of compounds bound to BTK^WT and provide a review of how the design of these inhibitors and PROTACs leads to a more selective inhibition and degradation of BTK. With the emergence of identified BTK resistance mutations, alternative strategies beyond established BTK inhibitors are fundamental for designing more selective inhibitors and degraders that can overcome resistance. Full article

The therapeutic potential of pharmacologically targeting kinases involved in regulating the DNA damage response (DDR) has been investigated for over two decades. Inhibitors of ATM, ATR, CHK1, CHK2 and WEE1 have been developed with the aim of subverting cell cycle checkpoint function in cancer cells, promoting cell death. The DNA repair pathway non-homologous end-joining can also be targeted through DNA-PK inhibition. However, despite extensive preclinical and clinical studies, none of the many candidate inhibitors have yet made it through to clinical approval. Emerging evidence for tumour biomarkers associated with enhanced sensitivity to DDR kinase inhibition may provide a way through this impasse. Clinical testing in appropriately stratified cohorts is now becoming increasingly common, with some promising results. Building on results obtained with small-molecule inhibitors, targeted protein degradation (TPD) utilising proteolysis-targeting chimaeras (PROTACs) or molecular glues for degradation of DDR kinases is a rapidly developing strategy. This review discusses the current ATM, ATR, DNA-PK, CHK1, CHK2 and WEE1 inhibitors that show the most promise as monotherapies and combination treatments in solid tumours, as well as the potential benefits of using TPD technology over small-molecule inhibitors. Established and emerging biomarkers that can be applied to patient selection are also discussed. Full article

Background/Objectives: Cancer resistance, pathway redundancy, and compensatory signaling challenge traditional therapies. Dual target strategies address this by engaging two disease-relevant proteins within a single molecule. This review compares classical dual inhibitors with dual proteolysis-targeting chimeras (dual PROTACs) to evaluate the therapeutic advantages of degradation over occupancy. Methods: We examine oncology target pairs featuring documented examples of both dual inhibitors and dual PROTACs. The biological rationale for co-targeting is analyzed alongside a comparative assessment of their chemical frameworks, focusing heavily on the synthetic strategies, length, and structure of linkers required for dual PROTAC ternary complex formation. Results: While dual inhibitors rely on active-site occupancy, dual PROTACs leverage the ubiquitin–proteasome system for catalytic target elimination. Transitioning from dual inhibition to dual degradation in most cases (>85%) enhances antitumor efficacy, extends duration of action, and overcomes resistance mutations. Optimizing linker design remains the critical factor in balancing the simultaneous degradation kinetics of two distinct proteins. Conclusions: Dual PROTACs provide distinct advantages over traditional inhibitors by completely destroying target proteins rather than merely blocking them. This comparison offers a practical entry point and actionable synthetic strategies for medicinal chemists designing multi-target protein degraders. Full article

Background/Objectives: Fusion-positive rhabdomyosarcoma (FP-RMS) is characterized by the presence of tumor-specific chromosomal translocation products, most commonly PAX3::FOXO1, and typically results in lower survival rates compared to fusion-negative RMS cases. PAX3::FOXO1 plays a critical role in FP-RMS oncogenesis in both tumor initiation and maintenance, making it an excellent target for therapeutic intervention in FP-RMS. Methods: We created Proteolysis Targeting Chimeras (PROTACs) by combining PAX3::FOXO1-binding small molecules with E3 ligase recruiters for cereblon (CRBN) or S-Phase Kinase Associated Protein 1 (SKP1). Results: The PROTACs achieved up to 70% degradation of the endogenous PAX3::FOXO1 protein in FP-RMS cell lines in a concentration-, time-, and proteasome-dependent manner. Moreover, the PROTAC-mediated targeted degradation of PAX3::FOXO1 in FP-RMS cells deregulated the endogenous PAX3::FOXO1 gene expression signature and induced myogenic differentiation. Importantly, treatment of FP-RMS cells with PAX3::FOXO1-PROTACs synergized with vincristine treatment and impaired >80% of anchorage-independent growth in soft agar. Conclusions: Taken together, we demonstrate the proof of principle of PROTACs targeting the oncogenic fusion protein PAX3::FOXO1 in FP-RMS cells. The PROTACs created in this study will not only be useful tools in studying PAX3::FOXO1 biology in laboratory models but could also serve as molecular scaffolds for designing clinical-grade molecules to assess the therapeutic potential of PAX3::FOXO1-targeting PROTACs in FP-RMS patients. Full article

Vascular dementia (VaD) represents a spectrum of neurodegenerative disorders driven by chronic or acute cerebral hypoperfusion, converging on the structural collapse of the neurovascular unit (NVU). While vascular mechanics and neuroinflammation have been extensively characterized, the extracellular matrix (ECM) remains an under-appreciated driver of this pathology. Far from being a passive scaffold, the ECM serves as a dynamic regulator of brain homeostasis, governing the integrity of the blood–brain barrier (BBB), supporting synaptic plasticity via Perineuronal Nets (PNNs), and facilitating the glymphatic clearance of metabolic waste. This review and perspective examines the pivotal role of the ECM within the “tripartite” NVU, the interface connecting vascular cells, CNS glia, and perivascular nerves. We discuss how the dysregulated activity of matrix metalloproteinases (MMPs) and the alteration of basement membrane components compromise the architectural defenses of the NVU. We describe how these structural failures can transform vascular insults into progressive neurodegenerative decline by unmasking inflammatory binding sites and disrupting cell–matrix signaling. Specifically, we highlight (1) the physiological architecture of the NVU and its dependence on specific collagen organization, (2) the mechanistic pathways of ECM disruption in VaD pathogenesis, including the feedback loop between ischemia and proteolysis, (3) the emerging therapeutic potential of targeting matrix components to restore neurovascular stability, and (4) a novel mechanochemical hypothesis framing pathological collagen functionalization as an epidemiological bimodal switch. Uncovering the interplay between structural remodeling and vascular function offers novel targets to halt the progression of dementia. Full article