Objective: This study aims to investigate the expression characteristics of GLUT10 in breast cancer and its role in mediating cisplatin resistance, with the goal of providing a new molecular target for personalized breast cancer treatment. Methods: Data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases were analyzed using the GEPIA2 platform to assess pan-cancer expression, while the UALCAN platform was used to analyze expression differences between breast cancer and normal breast tissues. In vitro, SK-BR-3 cells were divided into three groups: shScr (transfected with non-targeting scrambled shRNA), shSLC2A10#1, and shSLC2A10#2. MDA-MB-231 cells were divided into a vector control group and an SLC2A10 overexpression group. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect SLC2A10 mRNA expression. Western blotting was used to detect GLUT10 and cleaved caspase-3 protein expression. The CM-H2DCFDA probe was used to measure intracellular reactive oxygen species (ROS) levels. Drug sensitivity and colony formation assays were performed to evaluate cisplatin sensitivity, and flow cytometry was used to detect apoptosis rates. Results: GEPIA2 analysis showed that GLUT10 expression was downregulated in adrenocortical carcinoma, cervical squamous cell carcinoma and adenocarcinoma, and kidney chromophobe tumor tissues compared to normal tissues, whereas it was upregulated in invasive breast cancer, glioma, skin melanoma, and thymoma. UALCAN analysis revealed that SLC2A10 mRNA levels in breast cancer tissues were 1.85-fold higher than in normal breast tissues (P＜0.001). RT-qPCR results showed that SLC2A10 mRNA expression levels in breast cancer cell lines, ranked from high to low, were Hs 578T (160.5±12.3), SK-BR-3 (115.2±10.5), MDA-MB-468 (50.1±5.2), T-47D (35.4±4.1), and MCF7 (25.6±3.8), all significantly higher than in normal breast epithelial cells (P＜0.001). In SK-BR-3 cells, compared with the shScr group, the shSLC2A10#1 and shSLC2A10#2 groups exhibited increased intracellular ROS levels (relative fluorescence intensity: 1.78±0.12 and 2.05±0.15, respectively; P＜0.05), increased cisplatin sensitivity, reduced colony numbers, and promoted cisplatin-induced ROS accumulation and apoptosis. In MDA-MB-231 cells, compared with the vector control group, the SLC2A10 overexpression group showed decreased intracellular ROS levels (relative fluorescence intensity: 0.58±0.09, P＜0.05), decreased cisplatin sensitivity, and inhibited cisplatin-induced ROS accumulation and apoptosis. Conclusion: GLUT10 is highly expressed in breast cancer and mediates cisplatin resistance by regulating ROS levels, suggesting it may serve as a novel therapeutic target for reversing drug resistance in breast cancer.

Immunotherapeutic approaches for cutaneous squamous cell carcinoma (cSCC) remain limited to programmed cell death protein 1 (PD-1) blockade. Although genomics studies have characterized key driver mutations in cSCC, preclinical models that faithfully recapitulate both the genetic landscape and immune microenvironment of the human disease, that could drive the development of novel, effective therapies, are lacking.

Learning to Rank (LeToR) methods have gained increasing attention in drug response prediction, offering a direct way to prioritize effective treatments for cancer cell lines. In this study, we systematically benchmark six ranking loss functions, including state-of-the-art listwise methods, and five types of molecular representations across two large-scale drug screening datasets, CTRP and PRISM. Using high-dimensional gene expression profiles and various drug fingerprints and descriptors, we evaluated models under multiple validation setups and ranking metrics. Our results demonstrate that listwise loss functions such as LambdaLoss and LambdaRank consistently excel in both early and overall ranking quality. Additionally, combining molecular fingerprints with physicochemical descriptors yielded improved performance. A novel attention-based mechanism and a modified version of RankingSHAP were integrated to enhance interpretability, uncovering key genes and substructures aligned with known biological insights. The explainability pipeline successfully distinguished estrogen receptor-positive (ER⁺) and estrogen receptor-negative (ER-) breast cancer subtypes. The model successfully identified critical substructures in docetaxel, an FDA-approved therapy, and triptolide, which is currently undergoing clinical evaluation for breast cancer. These findings are consistent with established structure-activity relationship (SAR) data. Overall, this study presents a comprehensive evaluation framework and underscores the importance of carefully selecting loss functions and feature representations when developing robust and interpretable drug-ranking systems.

Fear of chemotherapy-induced side effects is a major concern among patients with cancer and may affect psychological well-being and treatment adherence. This methodological study aimed to translate, culturally adapt, and evaluate the psychometric properties of the Persian version of the Chemotherapy Side Effects Fear Scale (CheSeFS). The study was conducted from January to April 2024 at the Cancer Institute of Imam Khomeini Hospital Complex in Tehran, Iran, and included 600 patients undergoing chemotherapy. The CheSeFS underwent forward-backward translation and cross-cultural adaptation. Face and content validity, structural validity, convergent and discriminant validity, internal consistency, test-retest reliability, measurement error, a distribution-based MIC estimate, and factors associated with CheSeFS scores were evaluated. All statistical analyses were performed using Jamovi version 2.7.1 and included descriptive statistics, item analysis, exploratory factor analysis, confirmatory factor analysis, reliability and measurement error analyses, convergent and discriminant validity assessment, distribution-based MIC estimation, and regression analysis. Patient and expert evaluations supported face and content validity. Exploratory factor analysis identified a two-factor structure, including Physiological fear and Subjective or Psychological fear, explaining 54.4% of the total variance. Three items were removed during factor analysis, resulting in a final 11-item scale. Confirmatory factor analysis supported model fit, with χ²(df = 43) = 84.2, RMSEA = 0.06, CFI = 0.99, TLI = 0.99, and SRMR = 0.04. Internal consistency was satisfactory, with Cronbach's alpha = 0.89 for the total scale. Measurement error analysis showed an SEM of 1.64 and an MDC95 of 4.56, and the distribution-based MIC estimate was 1.01 points. The Persian 11-item CheSeFS demonstrated satisfactory validity and reliability for assessing chemotherapy-related fear among Iranian patients with cancer.

Developing highly selective PARP1 inhibitors is a promising strategy to improve the therapeutic window compared with dual PARP1/2 inhibitors. Through structure-guided design and optimization, we developed (R)-A17, a novel, highly selective PARP1 inhibitor featuring a unique tricyclic scaffold. It demonstrates nanomolar enzymatic potency (PARP1 IC50 = 2.4 nM), exceptional 65.8-fold selectivity over PARP2, and robust antiproliferative activity in BRCA-deficient cells. (R)-A17 exhibits favorable pharmacokinetic properties with complete oral bioavailability (F = 100%) in mice. Mechanistically, it selectively inhibits PARP1-mediated PARylation and induces DNA damage and G2/M phase arrest. In vivo, oral administration of (R)-A17 produced dose-dependent antitumor efficacy in BRCA mutant xenograft models, achieving tumor growth inhibition values of 57.8, 86.3, and 91.3% at doses of 0.3, 1, and 3 mg/kg, respectively, while also synergizing effectively with liposomal irinotecan in an HCT116 xenograft model. These results establish (R)-A17 as a promising candidate and validate the design strategy for the next-generation PARP1-targeted therapy.

WRN helicase activity inhibition has emerged as a promising therapeutic approach for targeting cancer cells with specific DNA repair deficiencies, especially those with microsatellite instability (MSI). Herein, we report a novel covalent WRN helicase inhibitor series discovered and optimized by leveraging insights from a covalent fragment investigation. Initial structure-based design led to potency-optimized compounds from this series that exhibited unbound cellular potency in the nanomolar range in both p21 induction and HCT116 CTG viability assays, albeit with high intrinsic warhead reactivity. Further refinement of the ADME properties by modulating the warhead reactivity yielded lead WC-2 with excellent cellular potency, low reactivity toward GSH, excellent plasma and blood stabilities, good oral bioavailability, and long in vivo half-lives in rat (T1/2 = 7.2 h; F = 62%) and dog (T1/2 = 18.9 h). WC-2 has the potential as a next-generation, low-dose WRN helicase clinical candidate for treating patients with MSI-classified tumors.

Despite recent therapeutic advances, treatment options for advanced, therapy-resistant, and metastatic prostate cancer (PCa) remain limited. Here, we developed and prospectively validated an integrated chemoinformatics and machine learning (ML) workflow with ligand-based similarity filtering. Validation on independent external data sets showed that this applicability-domain-guided integration strategy can reduce false positives and improve virtual screening performance. Screening of DrugBank identified five repurposing candidates with confirmed antiproliferative activity in both 2D and 3D PCa models. Among them, the antifungal agent chlormidazole emerged as the most promising candidate, displaying tumor-selective and predominantly cytostatic activity associated with p57 upregulation, reduced Rb phosphorylation, and G1 arrest. Chlormidazole also enhanced the antiproliferative activity of docetaxel in both models, achieving comparable efficacy at substantially lower docetaxel concentrations. These findings identify chlormidazole as a promising repurposing candidate for PCa and demonstrate the value of integrating chemoinformatics with ML for drug repurposing and virtual screening.

Chemotherapy-induced myelosuppression (CIM) significantly impairs hematopoiesis. Proanthocyanidin A1 (1) from peanut skin is a JAK2 activator to alleviate CIM, but the SAR and drug-like properties of Type-A proanthocyanidins remain unclear. Here, a series of Type-A proanthocyanidin derivatives (5-35) were designed, synthesized, and evaluated for JAK2 activation, leading to the identification of compound 32 as the most potent activator (EC50 = 64 nM). Target-binding assays demonstrated that 32 directly bound JAK2 and displayed preferential affinity for the JH2 pseudokinase domain over the JH1 catalytic domain, indicating a potential JH2-mediated activation mechanism. In primary BMHSCs, 32 activated the JAK2/STAT3 pathway and alleviated carboplatin-induced damage. Consistently, oral administration of 32 at 50 mg/kg activated JAK2/STAT3 signaling in vivo and promoted hematopoietic recovery in CIM mice, with favorable bioavailability and acceptable preliminary safety. These findings identify 32 as a promising orally available JAK2 activator for CIM treatment.

Microtubules are core cytoskeletal components for cellular activities. Their interaction with microtubule-associated protein 7 (MAP7) is crucial for cell proliferation, cellular component transport, and morphological regulation. The conserved microtubule surface region binds tightly to MAP7's microtubule-binding domain (MTBD). Its function relates closely to tumorigenesis and progression. Using structure-based drug design, we first designed peptides 1-3, peptide inhibitors targeting microtubule-MAP7 interaction. These peptides disrupt microtubule-MAP7 interaction by specifically binding to microtubules. After multiple optimizations, peptide-3's binding affinity to microtubules reaches 0.12 μM. Further studies show that it effectively inhibits the proliferation, migration, and invasion of colorectal cancer cells (HCT116 and SW480) and enhances cell damage. Animal experiments confirm its potent in vivo antitumor activity with no obvious toxicity. In summary, peptide-3 specifically disrupts microtubule-MAP7 interaction, acting as a promising lead compound for inhibiting colon cancer cell proliferation.

Resistance to monotherapy remains a major challenge in the treatment of nonsmall cell lung cancer (NSCLC), highlighting the need for innovative therapeutic strategies. To address this issue, we developed a dual-targeting strategy aimed at simultaneously inhibiting the oncogenic protein-protein interaction (PPI) between UBE2M and DCN1─which is critical for neddylation-dependent activation of cullin-RING ligases (CRLs)─and histone deacetylase (HDAC) activity. Inspired by the synergistic antitumor effects observed with combined inhibition of UBE2M-DCN1 and HDAC, we designed hybrid molecules integrating pharmacophores targeting both pathways. Our preferred compound JN210 effectively disrupts the UBE2M-DCN1 interaction and inhibits HDAC, demonstrating significantly enhanced cytotoxicity compared to the parent compounds in vitro and potent tumor growth suppression in vivo. Mechanistic studies revealed dual blockade of CRL neddylation and induction of histone hyperacetylation, resulting in impaired DNA damage repair and synergistic apoptosis. As a novel DCN1/HDAC dual inhibitor, JN210 represents a promising therapeutic candidate for NSCLC.

Decapping Scavenger (DcpS) enzyme, a pyrophosphatase involved in mRNA regulation via mRNA cap degradation, has been identified as a promising oncology target in fragile histidine triad (FHIT) deficient cancers such as AML and GBM but remains underexplored in broader solid tumor indications. We have discovered a novel DcpS inhibitor, compound 17, which has a differentiated binding mode relative to known inhibitors, engaging the second nucleotide-binding domain of the mRNA cap substrate. Compound 17 possesses superior levels of potency in NSCLC A549 cell line relative to known inhibitors and demonstrates excellent selectivity against DcpS-insensitive cell lines, high levels of bioavailability in preclinical species, and mitigated hERG liabilities. Finally, compound 17 demonstrates oral dose-dependent efficacy in two solid tumor xenograft models, A253 and EBC-1, highlighting the promise of DcpS as a novel target in FHIT low/deficient solid tumors.

Two copper(II) complexes, (1) [CuCl2(tmp-terpy)] and (2) {[CuCl(tmp-terpy)]·PF6}n, (tmp-terpy-4'-(3,4,5-trimethoxy-phenyl)-2,2':6',2″-terpyridine) were designed, characterized, and evaluated for cytotoxicity in 2D human cell models (HCT116, HCT116-DoxR, and in normal primary fibroblasts), and 3D colorectal cancer (CRC) spheroids and patient-derived organoids (PDOs). Both complexes demonstrated potent antiproliferative effects, alone and in combination with the FOLFOX (FF), across all 3D models. Importantly, the cytotoxic effects of complex 1 were significantly more pronounced in tumor-derived PDOs than in normal tissue-derived PDOs. Complex 1 induced reactive oxygen species (ROS) production, triggering intrinsic apoptosis and autophagy, consistent with a multimodal anticancer mechanism. It also exerted a cytostatic effect, as shown by delayed cell-cycle progression, and antiangiogenic activity in vivo without systemic toxicity. Notably, cotreatment of complex 1 with FF significantly potentiated cytotoxicity in 3D tumor spheroids and PDOs tumor-derived-PDOs. [CuCl2(tmp-terpy)] alone or in combination with the FF regimen warrants further evaluation in advanced preclinical models.

Estrogen receptor α (ERα) remains a pivotal therapeutic target for ER-positive (ER+) breast cancer, yet resistance to endocrine therapies driven by ligand-binding pocket (LBP) mutations demands novel strategies. To integrate the complementary strengths of binding modalities of the orthosteric LBP and the allosteric coactivator binding site (CBS) against endocrine resistance, we designed a series of ERα LBP/CBS dual-targeting proteolysis-targeting chimeras (PROTACs). The lead compound P5 demonstrated high binding affinities for LBP and CBS sites, potent antiproliferative activity, and efficient ERα degradation efficacy across a panel of breast cancer cell lines via the ubiquitin-proteasome system. Mechanistically, P5 triggered S-phase cell cycle arrest and apoptosis in LCC2 cells. In vivo, P5 exhibited significant tumor growth inhibition in the LCC2 xenograft model, with efficacy comparable to fulvestrant, and a favorable safety profile. Our findings validate the LBP/CBS dual-targeting PROTAC strategy as a promising avenue for overcoming resistance in ER+ breast cancer.

SHP2 (Src homology 2 (SH2)-containing protein tyrosine phosphatase 2) is a tyrosine phosphatase that plays a critical role in numerous physiological and pathological cellular processes, including cell proliferation, survival, and migration through the regulation of multiple signaling pathways, such as RAS-RAF-mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)-AKT, Janus tyrosine kinase (JAK), and signal transducer and activator of transcription pathways (STAT) in response to cytokines and growth factors. Through extensive structure-based optimization, we identified I-0436650, a preclinical candidate with an excellent pharmacological profile. I-0436650 is a low nanomolar allosteric inhibitor of human wild-type (wt) SHP2 and strongly inhibits ERK phosphorylation in cells. It exhibits antiproliferative activity in EGFR- and RAS-dependent cell lines, suppresses tumor growth as a single agent in xenograft models, and delays tumor relapse when combined with inhibitors of the same pathway, demonstrating the potential of vertical inhibition strategies.

Rho-associated coiled-coil-containing kinase 2 (ROCK2) is a key regulator of cellular motility and invasion and represents a promising therapeutic target for metastatic breast cancer. Through systematic structure-activity relationship (SAR) studies, we designed and synthesized a novel series of 1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione derivatives as selective ROCK2 inhibitors. Strategic deuterium incorporation during structural optimization was employed to enhance pharmacokinetic profiles. This effort led to the identification of compound 22d, a highly potent deuterated analog with excellent ROCK2 inhibitory activity (IC50 = 13 nM) and remarkable selectivity (≥769-fold over ROCK1). In functional assays, 22d exhibited robust antimetastatic activity in vitro and significantly suppressed tumor metastasis in MDA-MB-231 breast cancer xenograft models. Mechanistically, its antimetastatic effects were attributed to selective inhibition of STAT3 phosphorylation at tyrosine 705 (Y705). Collectively, these findings establish 22d as a novel lead compound that impairs breast cancer metastasis through targeted disruption of the ROCK2-STAT3 signaling axis, providing a promising foundation for further therapeutic development against metastatic breast cancer.

Selective lysine-specific demethylase 1 (LSD1) inhibition has emerged as a robust strategy for small cell lung cancer (SCLC) eradication. Herein, we describe the structural design, synthesis, and biological evaluation of novel reversible LSD1 inhibitors containing a carboxamido pyrazole core with a pyrrolidine-substituted phenyl ring. Notably, compound 10q demonstrated potent LSD1 inhibition with an IC50 value of 7.2 nM and effective H1417 cell growth inhibition with a GI50 value of 20.0 nM. Moreover, it showed notable selectivity against homologous proteins and demethylases. The oral administration of compound 10q demonstrated encouraging pharmacokinetic profiles and remarkable antitumor efficacy in the NCI-H1417 SCLC xenograft model using NOD/Shi-scid/IL-2Rγnull mice without notable toxicity. Furthermore, the potential of compound 10q is proposed by combinatorial therapy with chemotherapeutic agents for treating SCLC. Therefore, compound 10q can be considered a promising candidate as a selective and orally bioavailable LSD1 inhibitor.

Targeting methionine adenosyltransferase 2A (MAT2A) represents an attractive synthetic lethal approach for treating methylthioadenosine phosphorylase (MTAP)-deleted cancers. Despite promising progress in the development of MAT2A inhibitors, many reported compounds remain limited by insufficient selectivity, systemic toxicity, and the stereochemical complexities of atropisomerism. Through structure-guided optimization of our previously reported atropisomeric lead, we identified ZS97 (26), a potent MAT2A inhibitor that lacks axial chirality. The nonatropisomeric nature simplifies pharmacological development by avoiding the need for asymmetric synthesis or chiral resolution. ZS97 demonstrated potent enzymatic inhibition, effectively depleting intracellular SAM and suppressing downstream PRMT5-mediated methylation. This biochemical blockade selectively triggered the DNA damage response and cell growth inhibition in MTAP-deficient cancer cells. Furthermore, ZS97 exhibited favorable oral bioavailability and induced significant tumor inhibition in an NCI-H838 xenograft model without associated weight loss. These findings highlight ZS97 as a structurally optimized orally active candidate with therapeutic potential for MTAP-deficient cancers.

ADAR1 is an enzyme that catalyzes the conversion of adenosine to inosine, and its expression is dysregulated in various cancers. Based on the previously reported compound ZYS-1, we designed and synthesized a series of compounds to investigate structure-activity relationships (SAR) and identify novel adenosine analogues. Among these, compound H13 was found to exhibit potent antiproliferative activity against various cancer cell lines and selectively reduced ADAR1-mediated editing of APOBEC3D in a dose-dependent manner. Furthermore, compound H13 demonstrated favorable pharmacokinetic properties after oral administration (F = 31.97%) and significantly inhibited DU-145 and HUCCT1 tumor growth without apparent toxicities in vivo. These results support H13 as a promising lead compound for further development.

Activating mutations in the Kirsten rat sarcoma (KRAS) gene are prevalent oncogenic drivers in nonsmall cell lung cancer (NSCLC). Patients harboring KRAS-mutant lung cancers frequently develop central nervous system (CNS) metastases. Although approved KRAS G12C inhibitors (i.e., sotorasib and adagrasib) show promising clinical CNS activity, these agents demonstrate low preclinical brain-to-plasma ratios, raising the question of whether compounds with elevated preclinical Kp,uu,brain values might show enhanced clinical performance. Here, we report the first successful application of DNA-encoded library (DEL) screening technology to the identification of CNS-penetrant covalent inhibitors of KRAS G12C. In this effort, a property-biased covalent DEL-screening approach enabled the discovery of a structurally novel series of hydrogen bond donor-free KRAS G12C inhibitors with improved CNS exposure. Leveraging structure-based design, we refined this hit series to deliver lead compound AM-8719, a CNS-penetrant, orally efficacious KRAS G12C inhibitor exhibiting 200-fold improved potency with respect to initial screening hits.

Telomerase, responsible for extending telomeres and maintaining the malignant potential of tumors, has long been deemed a promising anticancer target. Nonetheless, because of its complex composition, the discovery of highly efficient telomerase inhibitors is a challenging task. Herein, we identify the blockage of telomerase assembly via targeting TCAB1 as a novel avenue for potent telomerase inhibition. Upon this strategy, (R)-(3,4-dimethoxyphenyl)(3-(3-hydroxypyrrolidin-1-yl)phenyl)methanone (R)-1b (IC50 = 2.04 nM), which directly targets TCAB1 and impairs telomerase assembly via obstructing the TCAB1-hTR interaction, has been discovered. Notably, its binding pocket and the critical residues are confirmed for further drug design. In vivo, (R)-1b remarkably sensitized tumors to small-molecule PD-L1 inhibitors and induced tumor regression, underscoring its potential for augmenting the efficacy of tumor immunotherapy. This study paves the way for the exploration of telomerase inhibitors with a distinctive mechanism of action via targeting TCAB1 and blocking telomerase assembly.