Chemical Biology & Drug Design最新文献

{"title":"An Anoikis-Related Gene Signature Associated With Stromal Remodeling and Clinical Outcome in Gastric Cancer","authors":"Zhijun Fu,&nbsp;Lin Sun,&nbsp;Xing Wang,&nbsp;Biao Cheng,&nbsp;Ying Huang,&nbsp;Yuzhu Tang,&nbsp;Zhihua Jin","doi":"10.1111/cbdd.70411","DOIUrl":"10.1111/cbdd.70411","url":null,"abstract":"<p>Gastric cancer (GC) remains a highly aggressive malignancy with poor prognosis. Anoikis resistance is closely associated with tumor progression and metastasis, but the prognostic and functional relevance of anoikis-related genes (ARGs) in GC remains incompletely understood. Public transcriptomic, clinical, somatic mutation, and single-cell RNA sequencing (scRNA-seq) datasets were integrated to identify differentially expressed ARGs, develop an ARG-based risk model, and investigate its associations with tumor microenvironment (TME) features. In vitro experiments were performed to assess the effects of selected candidate genes on GC cell migration and invasion. Forty-five differentially expressed ARGs were identified in The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohort. An ARG-based risk model was developed using the TCGA-STAD cohort and evaluated in the GSE84437 cohort. The model was associated with overall survival and provided potential value for risk stratification, although its discriminative performance was modest. High-risk patients showed distinct immune, stromal, and somatic mutational features. Single-cell analysis suggested that ARG-related transcriptional programs were associated with stromal remodeling and endothelial-to-mesenchymal transition (EndMT)-associated features in the GC microenvironment. Among the core ARGs, EEF1A2 and TAGLN showed prognostic relevance and higher protein expression in GC tissues. Small interfering RNA (siRNA)-mediated knockdown of either gene reduced the migration and invasion of HGC-27 cells. These findings indicate that ARG-related molecular features are associated with GC prognosis and immune-stromal characteristics, while EEF1A2 and TAGLN may represent candidate genes related to GC cell migration and invasion.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Single-Cell Transcriptomics, Multi-Omics Analyses, and Computational Pharmacology Reveal Macrophage Heterogeneity and the Putative THBS1-CD36 Axis in Coronary Atherosclerosis","authors":"Jianpeng Li,&nbsp;Xinrui Liu,&nbsp;Run Shi,&nbsp;Lin Yang,&nbsp;Rong Gu","doi":"10.1111/cbdd.70399","DOIUrl":"https://doi.org/10.1111/cbdd.70399","url":null,"abstract":"<p>Coronary atherosclerosis (CA) is characterized by profound macrophage heterogeneity that drives plaque progression and vulnerability, yet the precise subpopulations and their niche-specific functions remain incompletely defined. Here, we constructed a single-cell transcriptomic atlas of human CA using dataset GSE131778 and identified six distinct macrophage subpopulations. Among these, the THBS1+ macrophage subset emerged as a terminally differentiated, hypoxia-adaptive population with elevated TGF-β signaling and FOSB-driven transcriptional regulation. High-dimensional weighted gene co-expression network analysis revealed 12 transcriptional modules, with module NEW10 serving as a specific molecular signature of THBS1+ macrophages. Cell–cell communication analysis predicted a THBS1-CD36 ligand-receptor interaction potentially contributing to crosstalk between THBS1+ macrophages and lymphatic endothelial cells. Molecular docking and 100-ns molecular dynamics simulations predicted a thermodynamically favorable and conformationally stable interaction between SMS121 and CD36, providing an initial computational rationale for further experimental evaluation. Finally, leveraging the NEW10 module genes, we trained 13 machine learning classifiers to distinguish ACS from sCAD and evaluated their performance in differentiating ruptured from stable plaques; Support Vector Machine with linear kernel and Naive Bayes achieved the highest accuracy in an independent testing cohort, both attaining an AUC of 0.9333. These findings illuminate macrophage heterogeneity and intercellular communication in CA, identify the predicted THBS1-CD36 interaction as a candidate for further mechanistic and pharmacological investigation, and establish a macrophage-derived transcriptional signature for precise risk stratification.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70399","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzothiazepane-Based Curcumin Analogs Show Selective Effects on Respiration, Permeability, and Growth of Gut-Liver (Co-Culture) Cell Models","authors":"Fuhua Li,&nbsp;Julie De Munck,&nbsp;Felien Morlion,&nbsp;Katarina Magdalenic,&nbsp;Andreja Rajkovic,&nbsp;Matthias D'hooghe,&nbsp;John Van Camp,&nbsp;Charlotte Grootaert","doi":"10.1111/cbdd.70406","DOIUrl":"10.1111/cbdd.70406","url":null,"abstract":"<p>Curcumin, a natural polyphenol with anti-cancer potential, faces limitations due to metabolic instability, and non-specific toxicity. This study focused on four curcumin analogs (FM038, FM044, FM045, FM050) featuring oxobutenylidene-substituted benzothiazepane cores bearing pyridinyl or furan substituents. We systematically evaluated their selective toxic effect on human colon (Caco-2) and liver (HepG2) cells. This study reveals that structural modifications critically govern the selective cytotoxicity of curcumin analogs towards proliferating Caco-2 and HepG2 cells. Treatment with analogs featuring pyridin-2-yl substituents (FM045/FM050) resulted in a slightly reduced potency towards Caco-2 cells compared to curcumin, whereas FM044 (furan-2-yl) was non-toxic and FM038 (pyridin-3-yl, methylated core) maintained similar activity. In contrast, direct exposure to proliferating HepG2 cells resulted in less cytotoxicity compared to the Caco-2 cell line, which points to a cell-specific mode-of-action in growing cells. When combined in a co-culture, metabolites generated and/or transported by differentiated Caco-2 cells significantly decreased HepG2 viability at an apical concentration of 15 μM. Efflux analysis of respiration and acidification showed that FM050 induced the strongest mitochondrial dysfunction in Caco-2 cells, directly driving cytotoxicity, whereas HepG2 toxicity correlated with intrinsic detoxification capacity rather than mitochondrial disruption. A metabolic shift towards glycolysis was observed in both cell lines, indicating energy pathway modulation to a more dysfunctional phenotype. These findings highlight the dual role of structural optimization (e.g., methylation, heterocyclic substituents) for (cancer) cell-specific bioactivity and colonic metabolism and may guide future development of curcumin-based chemopreventive agents after in vivo validation and metabolite characterization.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149019191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, Antimycobacterial Evaluation, and In Silico Investigation of Benzisothiazole-Based Hydrazide Derivatives as Potential Anti-Tuberculosis Agents","authors":"Vivek Sharma,&nbsp;Arun Sharma,&nbsp;Ruchi Poria,&nbsp;Pardeep Kumar","doi":"10.1111/cbdd.70405","DOIUrl":"https://doi.org/10.1111/cbdd.70405","url":null,"abstract":"<p>A series of novel benzisothiazole-based hydrazide derivatives was rationally designed, synthesized, and evaluated for their antitubercular activity. Among the synthesized compounds, derivative <b>8k</b> emerged as the most potent candidate, exhibiting a minimum inhibitory concentration (MIC) of 0.25 μg/mL, along with a high selectivity index (SI) of 42 and confirmed bactericidal activity. To gain preliminary insights into its possible mechanism of action, compound <b>8k</b> was subjected to molecular docking and 100 ns molecular dynamics simulations, using enoyl-acyl carrier protein reductase (InhA) as the proposed molecular target. The computational studies revealed favorable binding interactions and a relatively stable protein–ligand complex, suggesting InhA as a potential molecular target. However, experimental target-validation studies are required to confirm direct InhA inhibition and establish the proposed mechanism of action. Furthermore, in silico ADMET predictions indicated favorable pharmacokinetic characteristics and drug-likeness properties for the lead compound. Collectively, these findings highlight the potential of benzisothiazole-based hydrazide derivatives as promising scaffolds for the development of new antitubercular agents.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70405","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148994305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Synthesis of Novel 1,2,3-Triazole Conjugates Featuring Hydroxamic Acid and Sulfonamide Moieties: Exploring Dual Pharmacophores for Enhanced Biological Activity","authors":"Dineshkumar Pagar,&nbsp;Ranjay Shaw,&nbsp;Hemant Suryavanshi,&nbsp;Dhanji Rajani,&nbsp;Sudhakar Patil","doi":"10.1111/cbdd.70400","DOIUrl":"10.1111/cbdd.70400","url":null,"abstract":"<p>A new series of <i>N</i>-hydroxy-1-(4-(aryl sulfonamido)phenyl)-1<i>H</i>-1,2,3-triazole-4-carboxamide derivatives (<b>8a</b>-<b>j</b>) were synthesized through a concise multistep route integrating three key pharmacophores: the 1,2,3-triazole core, an aryl sulfonamide moiety, and an <i>N</i>-hydroxycarboxamide group. Biological evaluation demonstrated promising antimicrobial potential for several derivatives. Compounds <b>8f</b>, <b>8g</b>, and <b>8i</b> exhibited notable antibacterial activity against both Gram-positive and Gram-negative bacteria, whereas most analogues showed weak antifungal activity. In the antimalarial assay, compound <b>8d</b> emerged as the most potent derivative (IC₅₀ = 0.84 μg/mL), while compounds <b>8b</b>, <b>8e</b>, <b>8g</b>, and <b>8h</b> also displayed appreciable activity. Antitubercular evaluation identified compounds <b>8g</b> and <b>8i</b> as the most active derivatives against <i>Mycobacterium tuberculosis</i> H37Rv, with MIC values of 62.5 and 50 μg/mL, respectively. The molecular docking study against DNA gyrase (PDB ID: 7FVT) and lanosterol 14α-demethylase (PDB ID: 5V5Z) as relevant antibacterial and antifungal targets, respectively, showed a similar trend of activity. Computational studies, including molecular docking, MM/GBSA, molecular dynamics simulations, and ADME prediction, supported the structural and pharmacokinetic characteristics of the synthesized compounds, with selected derivatives exhibiting favorable interactions with the c-KIT kinase active site and generally acceptable drug-like properties. Overall, these triazole–sulfonamide–N-hydroxycarboxamide hybrids represent promising lead molecules for further structural optimization and biological investigation.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70400","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, Structural Characterization, and Investigation of Biological Effects of Novel Benzothiazole-Triazole Derivatives Designed as AKT Kinase Inhibitors","authors":"Bilge Çiftçi,&nbsp;Zeynep Gülenç,&nbsp;Büşra Korkut Çelikateş,&nbsp;Derya Osmaniye","doi":"10.1111/cbdd.70404","DOIUrl":"10.1111/cbdd.70404","url":null,"abstract":"<p>Breast cancer (BC) is one of the most common cancers in women worldwide, and the need for new, more effective treatment options remains. The PI3K/Akt signaling pathway and the aromatase enzyme are among the molecular targets that play a critical role in the development and progression of BC. In this study, novel benzothiazole-triazole derivatives were synthesized, and their structures were confirmed using NMR and HRMS analyses. The cytotoxic activities of the eight synthesized compounds in the MCF-7 <span>BC</span> cell line were evaluated using the MTT method, with NIH/3T3 cells used as a healthy cell model. The IC₅₀ values of the compounds ranged from 10.186 to 52.020 μM, with compounds <b>5b</b>, <b>5f</b>, and <b>5h</b> showing the highest activity. Selectivity index results revealed that compound <b>5h</b> (SI = 5.986) exhibited the optimal selectivity profile along with strong anticancer activity. In enzyme inhibition studies, compound <b>5h</b> showed a strong inhibitory effect on Akt1, exhibiting activity close to the reference inhibitor with an IC₅₀ value of 0.209 ± 0.011 μM. However, the lack of significant inhibition of aromatase enzymes indicated that the compound displayed a more selective inhibitory profile towards Akt1. Mechanistic studies revealed that compound <b>5h</b> induced apoptotic cell death in MCF-7 cells, disrupted mitochondrial membrane potential, and caused high levels of caspase-3 activation. Furthermore, molecular docking and molecular dynamics simulations showed that the compound formed stable interactions in the Akt1 and PI3K active sites, supporting the experimental results. The findings indicate that compound <b>5h</b> is a promising anticancer candidate that targets the PI3K/Akt signaling pathway.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOC1-Associated VLDL-Pathway Dysregulation in Papillary Thyroid Carcinoma: A Reproducible Cross-Cohort Transcriptomic Signature Associated With the Diagnostic-to-Treatment Interval","authors":"Yinfeng Li,&nbsp;Ge Meng,&nbsp;Min Peng,&nbsp;Guangyan Chen,&nbsp;Yin-Ping Zhang","doi":"10.1111/cbdd.70403","DOIUrl":"10.1111/cbdd.70403","url":null,"abstract":"<p>The diagnostic-to-treatment interval (DTI) of papillary thyroid carcinoma (PTC) has long been regarded as an inactive administrative period. We expected to find that DTI is a window of high metabolic activity where apolipoprotein dysregulation may lead to harm. A four-phase integrated design was used. Phase 1 analysed transcriptomic and clinical data from TCGA-THCA (<i>n</i> = 209) to find DTI-associated molecular alterations, and used a maximally selected rank statistic to set the optimal time window. Phase 2 verified the lipoprotein signature in three independent GEO cohorts (GSE29265/GSE33630/GSE60542). Phase 3 used XGBoost regression in conjunction with SHAP (SHapley Additive exPlanations) to explore gene–gene interactions and predictive structures. Phase 4 used two-sample Mendelian randomization to determine whether genetically determined levels of the 233 metabolic biomarkers were associated with PTC. A 77-day threshold optimally stratified postoperative complete response rates (91.5% for DTI ≤ 77 days vs. 79.0% for DTI &gt; 77 days; <i>p</i> = 0.035). Differential expression analysis found 77 genes that were significantly associated with prolonged DTI, and the enriched pathways included PPAR signalling, fat digestion and apolipoprotein particle dynamics. Linear regression showed that longer DTI was associated with higher expression of APOA1 and APOC1. XGBoost–SHAP analysis showed that APOA1 and APOC1 were the top predictive features, and their interaction explained most of the non-additive variance. Cross-cohort validation showed that APOC1 and LPL were consistently upregulated and VLDLR was downregulated in all GEO datasets. Disease-state predictive model building found that the LPL–APOC1 axis effectively distinguished tumour from normal tissue. In two-sample MR analysis of 233 metabolic traits, genetically predicted VLDL and triglyceride-rich lipoprotein traits showed a predominantly risk-increasing direction of effect, and HDL cholesterol exhibited a protective effect, which was consistent with the transcriptomic results; however, no individual exposure remained significant after multiple testing correction in either outcome dataset, so the genetic analysis provided support for and extended the hypothesis rather than confirming it. Based on the above analysis, the pre-operative period of PTC may be metabolically active rather than quiescent; however, this has not been confirmed in future studies. Dysregulation of the APOC1-associated VLDL pathway is a reproducible cross-cohort transcriptomic signature in PTC; although genetic analysis has been conducted directionally, strong causal evidence has not been obtained. Therefore, at the same time, we will shift from time-limited to metabolically targeted preoperative risk assessment.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148972762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, and Investigation of the Biological Activities of New Thiadiazole Derivatives With Anticancer Effects","authors":"Yusuf Özkay,&nbsp;Enes Bal,&nbsp;Berkant Kurban,&nbsp;Derya Osmaniye,&nbsp;Begüm Nurpelin Sağlık Özkan,&nbsp;Zafer Asım Kaplancıklı","doi":"10.1111/cbdd.70398","DOIUrl":"10.1111/cbdd.70398","url":null,"abstract":"<p>Breast cancer is one of the most significant diseases in today's world. Hormone-dependent breast cancers constitute a significant portion of breast cancers. A series of thiadiazole derivative compounds have been designed to provide a rational alternative to aromatase inhibitors, which are actively used in related cancer treatments. The designed compounds were synthesized in three steps, and their structures were elucidated using ¹H-NMR, ¹³C-NMR, and HRMS spectroscopic methods. The inhibitory potentials of the obtained compounds were investigated using in vitro and in silico methods. In the studies conducted, compound <b>3c</b> stood out with its scores and values. Compound <b>3c</b> demonstrated inhibitory activity with an IC₅₀ of 4.896 ± 0.210 μM against the tested cell line and an IC₅₀ of 0.078 ± 0.003 μM against aromatase.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Multi-Omics and Radiogenomic Analysis Identifies S100B and ITGB5 as Complementary Candidate Biomarkers of Glioblastoma Heterogeneity","authors":"Xuhang Yang,&nbsp;Yusong Zhang,&nbsp;Yutuo Zheng,&nbsp;Jian Lin","doi":"10.1111/cbdd.70396","DOIUrl":"10.1111/cbdd.70396","url":null,"abstract":"<p>Glioblastoma (GBM) is characterized by marked intratumoral heterogeneity, diffuse invasion, and a profoundly immunosuppressive tumor microenvironment. In this study, we applied an integrative multi-omics and radiogenomic framework to identify candidate biomarkers reflecting complementary dimensions of GBM heterogeneity. Public bulk transcriptomic datasets were integrated to define GBM-related differentially expressed genes, which were intersected with curated microbiota-associated gene sets as a hypothesis-generating screening strategy. Machine-learning models with SHAP interpretation were used for candidate-gene prioritization, followed by survival-association analysis, pan-cancer comparison, Human Protein Atlas immunohistochemistry, CPTAC proteomics, immune infiltration analysis, single-cell transcriptomics, spatial transcriptomics, in silico perturbation analysis, and MRI-based radiogenomics. GBM samples showed enrichment of extracellular matrix organization, proliferative programs, immune-related signaling, and vascular or endothelial pathways, with relative reductions in neural, synaptic, and myelin-associated signatures. S100B and ITGB5 emerged as survival-associated candidate markers with different biological contexts. Multi-omics analyses suggested that S100B may reflect broadly distributed glial-lineage and malignant-state programs, whereas ITGB5 was more closely associated with focal extracellular matrix remodeling, stromal-vascular interactions, and immunoregulatory niches. Radiogenomic analysis further suggested distinct MRI-derived associations for the two genes, with the ITGB5-related model retaining a broader radiomic signature and showing a more heterogeneous habitat pattern than the S100B-related model. These exploratory findings support S100B and ITGB5 as complementary candidate biomarkers of GBM heterogeneity and provide a basis for future experimental, multicenter, and prospective validation.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148972254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, Biological Studies and Putative Binding Mode of Novel Benzotriazolothalidomide Derivatives as Cereblon Ligands","authors":"Pramit Ganguly,&nbsp;Mrinalkanti Kundu,&nbsp;Tonmoy Sarkar,&nbsp;Gillian Dcosta,&nbsp;Kankana Banerjee,&nbsp;Ritama Banerjee,&nbsp;Arun K. Hajra,&nbsp;Sk Sahabuddin,&nbsp;Sohini Basu,&nbsp;Avratanu Das,&nbsp;Suparna Das,&nbsp;Rajib Barik,&nbsp;Md Ashif Ali","doi":"10.1111/cbdd.70394","DOIUrl":"10.1111/cbdd.70394","url":null,"abstract":"<p>Targeted protein degradation (TPD) represents a new paradigm in drug discovery, encompassing several innovative strategies like proteolysis targeting chimeras (PROTACs). PROTACs work by linking the target protein of interest (POI) to an E3 ubiquitin ligase, marking it for ubiquitination, and subsequent degradation by the proteasome. The ligand space of E3 ligase cereblon (CRBN) mostly includes phthalimide-based thalidomide 1 and its analogs, commonly known as cereblon E3 ligase modulators (CELMoDs) which have been approved for the treatment of multiple subtypes of non-Hodgkin's lymphoma (NHL). Recently, benzotriazolo thalidomide (4) was reported which displayed similar binding mode like thalidomide, having relatively stronger binding affinity. Towards our aim of identifying new generation CRBN binding ligands, which can have use either in PROTAC or CELMoD chemical space, systematic design and SAR studies around 4, synthesis, biological, and docking experiments to understand putative binding mode have been carried out. As a result, a few compounds were identified as potent CRBN ligands, including compound 13 having an IC₅₀ value of 198 ± 7 nM. Cell viability assay of benzotriazolothalidomide 13 in human embryonic kidney cells (HEK293) suggest a high level of safety profile (SI = &gt; 500). To showcase the drug likeness of this compound, it was tested in preliminary ADME assays, revealing its excellent aqueous solubility (161.87 ± 0.96 μM), and high in vitro metabolic stability in human liver microsome (CL_int, app = 16.57 ± 0.19 μL/min/mg of protein; T_1/2 = 104.57 ± 1.22 min) and thus offers the scope for further optimization of the compound.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}