Search Results (538)

Caseinolytic protease P (ClpP) is essential for maintaining mitochondrial protein homeostasis, and its activation has emerged as an attractive cancer therapeutic strategy. However, ONC201 is currently the only approved ClpP activator, and its low potency leads to high clinical doses, driving an urgent demand for highly potent agents. In this study, utilizing a ring-opening-based molecular simplification strategy, we identified a class of activators based on a novel piperidine-fused imidazolone scaffold. Through side-chain optimization, we ultimately obtained CLPP-3036 as a highly potent compound. CLPP-3036 exhibits nanomolar enzymatic potency (EC₅₀ = 6.02 nM, 146-fold more potent than ONC201) and excellent antiproliferative activity (MV4-11 IC₅₀ = 1.13 nM). Importantly, CLPP-3036 demonstrates significantly superior inhibitory activity compared to ONC201 across multiple hematologic and solid tumor cell lines, such as Raji cells (IC₅₀ = 9.8 nM, nearly 1260-fold more potent). Furthermore, CLPP-3036 promotes the degradation of ClpP substrate proteins and effectively triggers apoptosis in MV4-11 cells. Collectively, CLPP-3036 is a potent piperidine-fused imidazolone ClpP activator and represents a promising lead compound worthy of further study. Full article

Background: Hepatocellular carcinoma (HCC) remains challenging to treat because of the limited therapeutic efficacy and insufficient selectivity of conventional therapies. To overcome these limitations, multifunctional nanoplatforms integrating biomimetic strategies and combination therapy have attracted increasing attention. Single-modality therapies are often limited by insufficient therapeutic efficacy and restricted mechanisms of action, highlighting the need for biomimetic nanoplatforms that integrate combination therapeutic strategies for enhanced antitumor performance. Methods: Herein, a biomimetic strategy-based nanoplatform (DI-ZM) was constructed via a combination of ZIF-8 biomineralization, physical adsorption of dihydroartemisinin (DHA) and indocyanine green (ICG), followed by HepG2 cell membrane coating to achieve homologous interaction. This design enables integrated chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) within a single system. Results: The resulting DI-ZM nanoparticles exhibited a hydrodynamic diameter of approximately ~200 nm with good colloidal stability and high drug-loading capacity. Under 808 nm laser irradiation, DI-ZM achieved a temperature elevation to ~66 °C within 5 min, together with efficient ROS generation. Compared with uncoated nanoparticles, the biomimetic membrane coating significantly enhanced cellular uptake and homologous targeting ability, as confirmed by CLSM and flow cytometry analysis. Benefiting from the biomimetic membrane coating, DI-ZM further exhibited improved homologous targeting and cellular uptake, which contributed to enhanced intracellular ROS generation. This was accompanied by significant mitochondrial membrane depolarization and apoptosis rates exceeding 80% in HepG2 cells under laser irradiation, ultimately resulting in markedly enhanced cytotoxicity. In addition, the biomimetic membrane coating also enabled efficient penetration of DI-ZM into multicellular tumor spheroids, indicating its improved tumor-penetration capability. In vivo antitumor studies further revealed effective tumor suppression with a tumor inhibition rate of approximately 97%, along with acceptable systemic tolerance in HepG2 tumor-bearing mice. Conclusion: The biomimetic membrane-coated ZIF-8 nanoplatform integrating chemotherapy with ICG-mediated phototherapy (photothermal and photodynamic therapy) provides an effective strategy for the combination therapy against HCC. Full article

Background: As a key regulator of centrosome duplication, polo-like kinase 4 (PLK4) is abnormally overexpressed in various tumors and has emerged as an important target for the development of antitumor drugs. Methods: In this study, based on the lead compound ZSL-M001 (PLK4 IC50 = 3.0 μM) previously obtained by our research group, we designed and synthesized 28 novel quinazoline-based PLK4 inhibitors to enhance kinase inhibitory activity using side-chain extension strategies. Results: Among them, compound H24 (PLK4 IC50 < 0.1 nM) exhibited favorable in vitro antiproliferative activity against TRIM37-amplified MCF-7 breast cancer cells (MCF-7 IC50 = 2.37 ± 0.26 μM) and TRIM37-amplified neuroblastoma IMR-32 cells (IMR-32 IC50 = 1.28 ± 0.04 μM). Its activity was superior to that of the positive control LCR-263. Further in vitro biological evaluation demonstrated that H24 inhibited the colony formation of MCF-7 cells in a concentration-dependent manner, induced S/G2-phase cell-cycle arrest, and promoted apoptosis. H24 also showed favorable metabolic stability in human liver microsomes, with a half-life of 61.3 min. However, no obvious TRIM37 amplification-dependent cellular selectivity was observed in TRIM37 non-highly amplified A549 cells or normal human embryonic kidney HEK-293T cells. Given the suboptimal selectivity of the in vitro antiproliferative activity, Aurora kinase A, which shares high homology with PLK4, was selected for further evaluation of its selectivity. The IC50 for Aurora A inhibition was determined to be 151.2 nM, indicating that its broader kinase selectivity remains to be established. Conclusions: In summary, H24 is a highly potent biochemical PLK4 inhibitor and provides a useful lead scaffold for further optimization rather than a fully selective cellular candidate at the current stage. Full article

Glioblastoma (GB), the most prevalent and aggressive brain tumor, remains one of the most lethal challenges in modern oncology. Standard therapy remains largely ineffective, mainly due to limited therapeutic penetration across the blood–brain barrier (BBB) and adaptive tumor resistance. Consequently, there is an urgent need for innovative strategies to enhance therapeutic precision and efficacy. To address these limitations, we engineered a targeted peptide-based co-delivery system using the WRAP5 cell-penetrating peptide functionalized with a transferrin receptor (TfR)-targeting T7 peptide (sequence: HAIYPRH), enabling simultaneous delivery of temozolomide (TMZ) and a p53-encoding plasmid DNA. The resulting peptide-based TMZ/p53 nanocomplexes exhibited favorable physicochemical properties, enhanced TfR-mediated cellular uptake, and targeted antitumor activity mediated through p53-induced apoptosis in two-dimensional (2D) U87 MG cell cultures. To better reproduce the structural and cellular complexity of the tumor microenvironment, a three-dimensional U87 MG spheroid model was established and optimized using a Design of Experiments (DoE) approach to improve reproducibility and physiological relevance. The developed WRAP5-based nanocomplexes induced a significant dose-dependent inhibition of growth and morphological alterations in the U87 MG spheroid model, accompanied by deep penetration and cell death throughout the spheroid. Collectively, these findings highlight the potential of this targeted and tailored nanosystem to enhance cellular transfection, enable drug/gene co-delivery, restore p53 function, and promote apoptosis, representing a promising therapeutic strategy for GB treatment. Full article

Drug delivery systems (DDS) may improve the therapeutic performance of chemotherapy in lung cancer, but their preclinical efficacy has not been quantitatively synthesized. We conducted a systematic review and meta-analysis of controlled in vivo mouse studies evaluating DDS-based chemotherapeutic formulations for lung cancer. Databases were searched from inception to 15 February 2025, and methodological quality was assessed using the SYRCLE risk-of-bias tool. Thirty studies comprising 47 experiments were included. Compared with corresponding free-drug treatments, DDS-based chemotherapy significantly reduced tumor volume (WMD −310.67 mm³; 95% CI: −375.51 to −245.83; p < 0.001), although substantial heterogeneity was observed. Both targeted and non-targeted DDS were associated with tumor growth inhibition, and targeted formulations showed a larger average reduction; however, this finding should be interpreted in light of differences in formulation properties, tumor models, and treatment protocols. Nanoparticle, liposomal, and micellar platforms all demonstrated significant antitumor effects, while combination DDS and docetaxel- or cisplatin-based systems showed large effects in subgroup analyses with variable sample sizes. These findings support the continued development of DDS-based chemotherapy for lung cancer, but standardized reporting of nanocarrier characterization, pharmacokinetics, biodistribution, toxicity, and rigorous animal-study design is required to improve reproducibility and translational relevance. Full article

Background: Colorectal cancer (CRC) is driven by genetic alterations, epigenetic dysregulation and tumor microenvironment remodeling. Histone modification reader proteins serve as key epigenetic regulators of anti-tumor immunity, yet their synergistic immune networks, combined prognostic roles and immune subtype heterogeneity remain poorly understood. Methods: Here, we integrated multi-omics data and graph attention networks (GAT) to systematically screen prognostic-associated histone reader genes. We then conducted analyses using the immunoassay pipeline and ultimately identified hub immune-related genes validated in independent external cohorts. Additional analyses, including single-cell RNA sequencing (scRNA-seq), molecular docking and multiple in silico functional assays, were performed based on retrospective public datasets. Results: Four core genes (CUL7, GPC1, NFYA, SLC25A5) exhibited robust prognostic performance and strong correlations with anti-tumor immunity. Both core and auxiliary genes participate in critical metabolic and immune pathways. Candidate drugs present differential binding affinity for their encoded proteins, with sapitinib designated as a promising agent. Conclusions: This work constructs an epigenetic immune regulatory network and a four-gene signature, offering promising biomarkers and actionable therapeutic targets for precision immunotherapy against CRC. Full article

Podophyllotoxin (PPT) inhibits tumors such as lung cancer and breast cancer. However, it has poor water solubility and causes gastrointestinal dysfunction and bone marrow suppression, which severely limit its clinical application. Based on the differential reactive oxygen species (ROS) levels between tumor microenvironments and normal tissues, we designed and constructed a ROS-responsive micelle delivery system, successfully fabricating blank micelles (M) and PPT-loaded micelles (M@PPT). Both micelles exhibited good particle size uniformity, colloidal stability, and biosafety. The ROS responsiveness experiment revealed that, after incubating blank micelles (M) with 10 mM H₂O₂, the particle size increased significantly, and the size distribution broadened. High-performance liquid chromatography (HPLC) confirmed the release of cinnamaldehyde from the micelles upon H₂O₂ exposure. Additionally, DCFH-DA assays demonstrated that treatment with blank micelles (M) enhanced intracellular ROS levels. In vitro release studies showed that drug-loaded micelles (M@PPT) achieved 77.76% cumulative PPT release within 24 h in a buffer containing 10 mM H₂O₂, significantly exceeding the release observed in the H₂O₂-free control group. These results collectively validate the ROS-responsive disintegration of micelles and the subsequent release of cinnamaldehyde. The liberated cinnamaldehyde further amplified intracellular ROS levels, establishing a positive feedback loop that accelerated drug release. Cellular assays revealed superior tumor growth inhibition by M@PPT over free PPT, mediated through apoptosis induction, G2/M phase cell cycle arrest, downregulation of the anti-apoptotic protein Survivin, and upregulation of the p21 protein. In vivo studies further confirmed the enhanced antitumor efficacy and improved biosafety of M@PPT compared to free PPT. This ROS-responsive micellar system, by enabling tumor-targeted drug delivery and controlled release, provides a novel strategy to optimize the clinical utility of podophyllotoxin-based chemotherapeutics. Full article

Background: Geraniol is an acyclic monoterpene widely distributed in the essential oils of aromatic species such as Cymbopogon citratus, Pelargonium graveolens, and Rosa damascena, It is known for its antioxidant, anti-inflammatory, neuroprotective, and antitumor activities. Methods: This study aimed to investigate, through network pharmacology and computational ADMET modeling, the molecular mechanisms and pharmacological potential of geraniol, integrating drug-likeness parameters, toxicity prediction, and multitarget interactions. Results: A total of 25 core targets were identified, mainly involved in inflammation, oxidative stress, apoptosis, and transcriptional regulation. Geraniol exhibited a favorable drug-likeness profile, high predicted intestinal absorption, and low systemic toxicity, supporting its pharmaceutical applicability. Mechanistically, it modulates the Nrf2/HO-1 ↔ NF-κB axis, reducing reactive oxygen species, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and apoptotic markers (caspases, Bax), while enhancing antioxidant enzymes (SOD, CAT, GPx) and antiapoptotic proteins (Bcl-2). Conclusions: These findings confirm its multitarget and pleiotropic nature, highlighting its potential as a therapeutic candidate for inflammatory, metabolic, and neurodegenerative disorders. Furthermore, this study provides a robust mechanistic rationale for future in vitro and in vivo validation, as well as for the design of nanostructured formulations to improve geraniol’s bioavailability and therapeutic safety. Full article

Gastric cancer is among the leading causes of cancer-related deaths worldwide. Modern treatment approaches include nanoparticles (NPs) designed to target cancer cells, which release a therapeutic cargo facilitating the inhibition of their expansion, thereby improving anti-tumor therapies. The success of NPs, created to deliver anticancer agents and biologically active compounds, may depend on selecting the way to target cancer cells. This study focused on examining the effects of NPs made of polylactic acid (PLA) with histamine (His) end groups and loaded with 5-fluorouracil (5-FU), a known anticancer drug (PLA-His-5-FU), on human gastric cancer AGS cells in vitro. The incubation of AGS cells with PLA-His-FU NPs resulted in diminished mitochondrial membrane potential and the induction of cell apoptosis, along with cell cycle arrest and the reduction of cell proliferation. Furthermore, the NPs tested provoked the secretion of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β by AGS cells and induced the activation of the nuclear factor kappa B (NF-κB) signaling pathway in THP-1 blue monocytes, which indicates the ability to promote the development of a milieu for the infiltration and activation of immunocompetent cells. NPs did not increase intracellular adhesion molecule (ICAM-1) deposition on AGS cells, thus potentially preventing the distribution of cancer cells. In conclusion, PLA-His-5-FU NPs show promising anticancer activity for gastric cancer AGS cells in vitro, better than PLA-OH-5-FU, and can be used in further in vivo studies to confirm this activity. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) represents a compelling pharmacological target for the development of agents designed to circumvent tumor resistance to topoisomerase 1 (TOP1) inhibitors, a major class of clinically relevant antineoplastic drugs. This paper describes the design and synthesis of novel hybrid TDP1 inhibitors combining coumarin and monoterpene moieties via rigid isoxazole and 1,2,3-triazole heterocyclic linkers. The synthesis was accomplished via [3 + 2] cycloaddition of nitrile oxides to alkynes and copper-catalyzed click chemistry. Biological tests have demonstrated the crucial role of linker nature in the activity of the compounds. Isoxazole-linked conjugates showed strong inhibitory effects on TDP1, with IC₅₀ values in the submicromolar to low micromolar range (0.8–3.2 μM). Overall, these values slightly surpassed those of the triazole-linked analogues, whose IC₅₀ values ranged from 1.1 to 23.3 μM. At noncytotoxic doses, compounds 26e and 16b enhanced the sensitivity of human cervical cancer (HeLa) cells to the antitumor agent topotecan, a TOP1 inhibitor, thereby supporting the promise of this structural class as components of combination chemotherapy. Full article

Background: The highly heterogeneous and dynamically evolving tumor microenvironment leads to the development of drug resistance and recurrence in traditional therapies. Although immunotherapy demonstrates unique advantages, its clinical utility remains constrained by the suboptimal immunogenicity and the limited effect of monotherapy. Herein, a hybrid drug delivery system based on a spatiotemporal hierarchical controlled-release strategy was proposed to achieve dual immunotherapy with immune checkpoint blockade (ICB) and immunogenic cell death (ICD) to promote synergistic anti-tumor therapy. Methods: A liposome–micelle hybrid drug delivery system (RUT-RPP-LP) was constructed using a lipid bilayer composed of dioleoyl phosphatidylethanolamine/hemisuccinyl cholesterol to encapsulate rutin (RUT) and to form an inner cavity-encapsulated resveratrol micelle (RPP). RUT-RPP-LP was characterized, and its pH sensitivity and release behavior were investigated. Subsequently, a colon cancer tumor-bearing mouse model was constructed to evaluate the in vivo targeted anti-tumor effect and biological safety. On this basis, the combined mechanism of ICB and ICD was preliminarily explored. Results: RUT-RPP-LP possessed excellent formulation characteristics, stability, and biocompatibility, achieving graded controlled release of drugs via responding to the TME and lysosomal acidity, respectively. Obviously, RUT-RPP-LP could specifically target the tumor site, induce the occurrence of ICD, and simultaneously block the PD-1/PD-L1 immune checkpoint signaling pathway, thereby enhancing the function of T cells and inducing apoptosis of tumor cells. Conclusions: The RUT-RPP-LP based on the hierarchical controlled-release strategy exerted a spatiotemporally coordinated enhancement of anti-tumor immunity, and may provide a novel combinatorial approach to overcome the low response of immunotherapy in solid tumors. Full article

Background: Uveal melanoma (UM) represents the most prevalent primary intraocular malignancy in adults, yet patients harboring GNAQ/GNA11 mutations face particularly poor prognoses with median survival of merely 6–12 months following metastasis. Multi-targeted combination therapy offers a promising strategy to circumvent drug resistance. The present study investigated the synergistic anti-tumor efficacy and mechanistic basis of Isoliquiritigenin (ISL), Quercetin (Que) and Methylnissolin (Meth), three bioactive constituents from Astragalus membranaceus (Huangqi, a widely used traditional Chinese medicinal herb) against UM. Methods: Molecular docking and 100 ns molecular dynamics simulations assessed binding stability between the compounds and their respective targets (Gαq, MEK and YAP). Synergistic interactions were quantified using the Zero Interaction Potency (ZIP) model, a reference synergy model that compares observed combination effects to predicted non-interaction baselines across full dose–response matrices, based on CCK-8 assays. Cell cycle distribution, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry. Western blotting detected target proteins and apoptotic markers. A male BALB/c nude mouse xenograft model validated therapeutic efficacy and systemic safety. Results: Molecular docking revealed binding energies <−7.0 kcal·mol⁻¹ for all three drug–target pairs, with molecular dynamics trajectories confirming stable complex conformations (RMSD < 3 Å). In vitro, the ISL-Que-Meth (IQM) combination exhibited strong synergism (ZIP scores > 10), significantly increasing apoptotic rates, collapsing mitochondrial membrane potential and upregulating cleaved-caspase 9 expression compared with monotherapy, and a modest G2/M phase accumulation was also observed, although the magnitude was limited relative to apoptotic induction. In vivo, the triple combination achieved approximately 50% reduction in tumor growth compared with the control group, with effects comparable to or exceeding those of the clinical reference agent Trametinib, and reduced Ki67 proliferation indices while elevating cleaved-caspase 9 levels, without eliciting hepatorenal toxicity. While these data demonstrate therapeutic efficacy, they do not establish in vivo synergy, as single-agent and dual-combination arms were not included in the xenograft design. Conclusions: These findings demonstrate that IQM synergistically suppresses UM growth in association with coordinated modulation of Gαq/MEK/YAP axis components and caspase 9-dependent apoptosis via the intrinsic mitochondrial pathway, providing preclinical evidence for natural product-based multi-targeted therapy against UM. Full article

Background: The immunosuppressive tumor microenvironment (TME), driven by the CD39-mediated conversion of immunostimulatory ATP to immunosuppressive adenosine (ADO), limits cancer immunotherapy. Research design and methods: Here, we developed a nanoparticle (NP) for combined chemo-immunotherapy by co-delivering the ICD inducer doxorubicin (DOX) and a CD39 inhibitor (ARL67156). The amphiphilic polymer PEG2k-b-P(DMAEMA-co-DPAEMA)-b-PTDMAEMA self-assembled into NPs with stable drug loading and rapid, pH-triggered drug release in the acidic TME. Results: In vitro, NPs@DOX induced immunogenic cell death (ICD) and ATP release, while NPs/ARL effectively inhibited CD39. The co-loaded NPs (NPs@DOX/ARL) synergistically enhanced extracellular ATP accumulation by combining increased release with decreased degradation, leading to superior dendritic cell maturation. In vivo, NPs@DOX/ARL demonstrated enhanced tumor accumulation, significant tumor growth inhibition, and robust activation of anti-tumor T-cell immunity. Conclusions: This work presents a promising nanoplatform that targets the ATP-ADO axis to amplify ICD and reverse immunosuppression for enhanced cancer immunotherapy. Full article

Amino alcohols are a class of compounds bearing both amino and hydroxyl groups, ubiquitous in natural products and extensively utilized as key structural motifs in pharmaceuticals and functional materials. Owing to their structural diversity, inherent chirality, and high reactivity, they exhibit significant application value in the pharmaceutical field, materials industry, and organic synthesis. Compared with chemical synthesis, which suffers from limitations such as insufficient enantioselectivity, dependence on precious metal catalysts, and environmental concerns, biosynthesis offers core advantages of high stereoselectivity, mild reaction conditions, and environmental sustainability. This review systematically delineates the diverse applications of amino alcohols in the pharmaceutical field (e.g., anti-HIV, antimalarial, and antitumor drugs), materials industry (e.g., polymer modification and metal corrosion protection), and organic synthesis (e.g., chiral ligands and catalysts). Particular emphasis is placed on the biosynthetic strategies and pathways of representative amino alcohols, including ethanolamine, (2S,3R)-2-amino-1,3,4-butanetriol, (R)-3-amino-1-butanol, sphingosine, and metaraminol, as well as the metabolic engineering design principles and downstream processing technologies for amino alcohol biosynthesis. Although current biosynthetic approaches still face bottlenecks in enzyme catalytic efficiency, substrate tolerance, cofactor regeneration, product toxicity, and thermodynamic equilibrium, substantial improvements in synthetic efficiency and stereoselectivity have been achieved through protein engineering, metabolic engineering, in situ product removal, and multi-enzyme cascade optimization. This review aims to provide systematic theoretical references and technical insights for the green and efficient biomanufacturing of amino alcohols. Full article

Histone deacetylases (HDACs) are important epigenetic regulatory enzymes contributing to cancer proliferation, which could be critical targets in cancer therapy. The structural similarities of the existing HDAC inhibitors have resulted in an increase in the drug resistance. In this study, coumarin was employed as the core scaffold for structural derivatisation to develop a novel class of HDAC inhibitors based on computer-aided design (CADD). Their anti-tumor activity was evaluated against esophageal squamous cell lines. The results showed that most compounds exhibited potent anti-proliferative activity against KYSE70 and KYSE150. Among them, compound 4s and 4p exhibited the most potent activity with IC₅₀ values of 3.44 μM and 3.39 μM against KYSE70. To validate the target of the synthesized compounds, transcriptome sequencing was performed and the results revealed that a total of 487 genes were differentially expressed, including 190 up-regulated and 297 down-regulated genes. Among these, 79 genes were associated with the HDAC regulatory network, accounting for 16.2% of the differentially expressed genes. Molecular docking demonstrated that compound 4s could effectively enter the active site of HDAC, engaging with the cap group, zinc-binding group, and linker region. This multiple interaction network provides a structural basis for the potent inhibitory activity of compound 4s. In conclusion, a series of novel HDAC inhibitors with a coumarin scaffold were discovered, and their mode of action was revealed. This provides a valuable guide for the development of novel HDAC-targeting therapeutics. Full article