Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Design, synthesis and evaluation of pterostilbene-indole hybrids as potential anticancer agents","authors":"Yingjie Xiao ,&nbsp;Jiawei Tang ,&nbsp;Shuoyu Zeng ,&nbsp;Zhaoxia Liu ,&nbsp;Lingyu Li ,&nbsp;Zhongmei Zou ,&nbsp;Hai Shang","doi":"10.1016/j.bmcl.2025.130317","DOIUrl":"10.1016/j.bmcl.2025.130317","url":null,"abstract":"<div><div>Pterostilbene is a natural product that exhibits anticancer activity, primarily by targeting the jak/STAT3 signaling pathway. To enhance the anticancer efficacy of pterostilbene, a series of pterostilbene-indole hybrids were designed and synthesized via molecular hybridization with indole, aiming to develop novel STAT3 inhibitors, and preliminary structure-activity relationships (SAR) were established. Among them, <strong>18q</strong> exhibited potent antitumor activity with IC₅₀ values of 1.84 ± 0.41 μM (C6 cells) and 4.81 ± 1.12 μM (A549 cells). Flow cytometry analysis revealed its ability to promote late-stage apoptosis. Additionally, <strong>18q</strong> significantly suppressed tumor cell proliferation and migration, showing efficacy comparable to the positive control Vorinostat. It inhibited STAT3 phosphorylation, downregulated Bcl-2, and upregulated caspase-3, indicating apoptosis induction. The CETSA experiment showed that <strong>18q</strong> could stabilize the thermal degradation of STAT3, proving that it was a direct inhibitor of STAT3. In conclusion, <strong>18q</strong> is a promising STAT3 inhibitor with robust antitumor activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130317"},"PeriodicalIF":2.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and evaluation of 1,3,4-oxadiazole-based EGFR inhibitors","authors":"Zijun Tang ,&nbsp;Mingxing Hu ,&nbsp;Ye Gan ,&nbsp;Lin Wen ,&nbsp;Yijie Wang ,&nbsp;Yongmei Xie ,&nbsp;Mingqing Yuan","doi":"10.1016/j.bmcl.2025.130315","DOIUrl":"10.1016/j.bmcl.2025.130315","url":null,"abstract":"<div><div>The epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family, serves as a validated and significant therapeutic target in various cancers. EGFR inhibitors have substantially improved the treatment outcomes for patients with EGFR-positive tumors. The EGFR^T790M mutation has emerged as a leading cause of clinically acquired resistance to both first- and second-generation EGFR inhibitors. In this study, we integrated azoles, particularly 1,3,4-oxadiazoles, into a preferred quinazoline scaffold to design novel EGFR inhibitors. Compound <strong>4b</strong>, a new 1,3,4-oxadiazole-based EGFR inhibitor, demonstrated superior potency against the EGFR^L858R/T790M mutant (IC₅₀ = 17.18 nM compared to 733.20 nM for Erlotinib) and in NCI-H1975 cells (IC₅₀ = 2.17 ± 0.20 μM compared to 11.01 ± 0.05 μM for Erlotinib). Furthermore, <strong>4b</strong> significantly inhibited the migration of both A431 and NCI-H1975 cells and induced G1 phase cell cycle arrest in NCI-H1975 cells. In conclusion, these findings suggest that <strong>4b</strong> is a promising lead compound for the development of inhibitors targeting the EGFR^L858R/T790M mutation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130315"},"PeriodicalIF":2.5,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of naphthoaurones against colon cancer cells","authors":"Youngshim Lee ,&nbsp;Seunghyun Ahn ,&nbsp;Dongsoo Koh ,&nbsp;Yoongho Lim ,&nbsp;Euitaek Jung ,&nbsp;Soon Young Shin","doi":"10.1016/j.bmcl.2025.130313","DOIUrl":"10.1016/j.bmcl.2025.130313","url":null,"abstract":"<div><div>To identify compounds with potent inhibitory effects on HCT116 colon cancer cells, naphthoaurone compounds were designed and synthesized. A clonogenic survival assay was performed for the 16 synthesized compounds as an initial investigation, and compound <strong>8</strong> was selected based on its half-maximal HCT116 colon cancer cell growth inhibitory effect (1.11 μM). Further biological experiments for compound <strong>8</strong> demonstrated a significant decrease in the survival rate of HCT116 cells at the dose exceeded 10 μM, reaching an effective dose for a 50 % reduction in viability (ED₅₀) of 24.62 μM. Cell cycle analysis revealed that the sub-G1 cell population, a common feature of cells undergoing apoptosis, increased with a decrease in the G1 phase and an increase in G2/M phase cells after exposure to compound <strong>8</strong>. Moreover, over time, compound <strong>8</strong> activated caspase-2, caspase-9, and caspase-3 <em>via</em> proteolytic cleavage. These results indicated that compound <strong>8</strong> triggered apoptotic cell death in HCT116 colon cancer cells by activating caspase-mediated apoptosis. In conclusion, a novel naphthoaurone derivative, (<em>Z</em>)-6-methoxy-2-((2-methoxynaphthalen-1-yl)methylene)benzofuran-3(2<em>H</em>)-one), shows potential for use in colon cancer therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130313"},"PeriodicalIF":2.5,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of hPIF1 helicase inhibitors by virtual screening of a Fsp3-enriched library","authors":"Mark J.A. Wever ,&nbsp;Francesca R. Scommegna ,&nbsp;Jean-François Poisson ,&nbsp;Vincent Rodeschini ,&nbsp;Didier Roche ,&nbsp;Cyril M. Sanders","doi":"10.1016/j.bmcl.2025.130314","DOIUrl":"10.1016/j.bmcl.2025.130314","url":null,"abstract":"<div><div>The PIF1 DNA helicase has functions in genome stability and there is strong evidence for a relation between elevated human PIF1 expression and poor outcomes in cancer patients. Here, we report the discovery, <em>via</em> sequential structure-based virtual screening, of a novel series of compounds that inhibit human PIF1 helicase activity. One active scaffold was identified and confirmed <em>in vitro</em>. Molecular modelling-based design and chemical synthesis ultimately led to the 2,6-diaminopyridine derivative <strong>48</strong> inhibiting hPIF1 with an IC₅₀ of 320 μM. Our results indicate that the new scaffold of <strong>48</strong> selected from virtual screening exhibits potential as a starting point for novel hPIF1 inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130314"},"PeriodicalIF":2.5,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual CDK6 and CDK9 inhibitors as anti-psoriasis agents: Design, synthesis, and anti-inflammatory activity","authors":"Yiming Ru ,&nbsp;Fang Zhao ,&nbsp;Haojie Zuo ,&nbsp;Xiuxiu Gao ,&nbsp;Yaoyao Yan ,&nbsp;Xiaodong Ma ,&nbsp;Yang Wang","doi":"10.1016/j.bmcl.2025.130316","DOIUrl":"10.1016/j.bmcl.2025.130316","url":null,"abstract":"<div><div>Skin hyperplasia and aberrant secretion of inflammatory factors are typical features of psoriasis. Given the cooperative role of CDK6-mediated cell proliferation and CDK9-mediated disturbance of inflammatory cytokines in the progression of psoriasis, dual inhibition of CDK6 and CDK9 is expected to not only exert synergetic anti-psoriatic effects but also reduce the toxicity of single-target inhibition. In this study, on the basis of our previously discovered lead, a total of 17 final compounds were designed and synthesized for exploring additional hydrogen bond interactions with hydrophilic residues in the inner pocket of CDK6 or CDK9. Among them, <strong>4</strong>, with dual CDK6 and CDK9 inhibitory activities, was capable to ameliorate inflammation <em>in vitro</em>. Furthermore, it inhibited the activation of STAT3 pathway and decreased the mRNA levels of inflammatory factors in IFN-γ/TNF-α-induced HaCaT cells. These findings indicate dual CDK6 and CDK9 inhibitors may emerge as potential therapeutic agents for psoriasis.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130316"},"PeriodicalIF":2.5,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144365950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent progress in synthetic strategies to develop potent, HDAC8-selective, small-molecule inhibitors","authors":"Brandon D. Lowe ,&nbsp;Steven Fletcher","doi":"10.1016/j.bmcl.2025.130312","DOIUrl":"10.1016/j.bmcl.2025.130312","url":null,"abstract":"<div><div>Key players in epigenetic control, the 11 zinc-dependent histone deacetylase (HDAC) enzymes have been affirmed as therapeutic targets, particularly in the discovery of new chemotherapy drugs: currently there are 3 FDA-approved pan-HDAC inhibitors (HDACi's), although these are not without their side effects. It has been rationalized that achieving HDAC isoform-selective inhibitors may yield safer drugs. HDAC8 has recently been validated as a novel target for the treatment of (pediatric) neuroblastoma, and its overexpression has been implicated in a range of other diseases. Herein, we discuss the topology of the HDAC8 active site in the context of inhibitor design, and we present recent progress in the discovery of potent, HDAC8-selective small-molecule inhibitors, with a discussion on the particular structural criteria required. HDACi's largely conform to a canonical pharmacophore model of a capping group connected <em>via</em> a linker to a zinc binding group (ZBG), which is typically a (potentially mutagenic) hydroxamic acid. In particular, for HDAC8-selectivity, the small-molecule should adopt a geometric “L”-shape, which may be accomplished by the linker itself, or the linker and capping group. More recently, HDAC isoform selectivity has been realized with hydroxamic acid surrogates, such as <em>ortho</em>-aminoanilides that yield potent and HDAC1-3-selective (but HDAC8-inactive) inhibitors. Hydrazides have long been utilized as bioisosteres of hydroxamic acids in HDAC inhibitor design, but a recent re-visiting explored the attachment of alkyl groups, and an <em>n</em>-hexyl substituent on the distal, non-acylated nitrogen affords potent and selective HDAC8 inhibitors probably through targeting the foot pocket of the active site; this discovery was observed across three different HDACi scaffolds, and thus appears quite general. α-Aminoketo ZBGs have also demonstrated HDAC8-selectivity, with associated benzylic moieties likewise engaging the foot pocket. We speculate that a re-imagining of the ortho-aminoanilide ZBG through a careful and methodical survey of related moieties, may lead to the discovery of additional HDAC8-selective ZBGs towards the realization of safe, pre-clinical inhibitors.</div><div>2025 Elsevier Ltd. All rights reserved.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130312"},"PeriodicalIF":2.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional evaluation of TIE2 activators identified in a model system using human umbilical vein endothelial cells","authors":"Saki Igarashi ,&nbsp;Koki Ishigami ,&nbsp;Naonori Uchida ,&nbsp;Eisuke Kato","doi":"10.1016/j.bmcl.2025.130311","DOIUrl":"10.1016/j.bmcl.2025.130311","url":null,"abstract":"<div><div>TIE2 (or TEK) receptor is a tyrosine kinase receptor important for maintaining vascular system function. Decreased TIE2 signalling associates with various diseases and deletion of TIE2 increases the risk of vascular diseases like atherosclerosis. Therefore, activators of TIE2 are suggested and shown to be efficient for maintaining healthy vascular systems and protect from diseases. We have previously explored several plant derived compounds as TIE2 activator using transiently expressed TIE2 in HeLa cells. In this study, we evaluated if the identified TIE2 activators, casuarinin, procyanidin tetramer (PC4), and morin, are capable to activate TIE2 signalling in human umbilical vein endothelial cells. We showed that casuarinin and PC4 activates AKT and ERK, the two kinase downstream of TIE2, and enhances tube formation in human umbilical vein endothelial cells. These results support the idea that the TIE2 activators identified in the TIE2-expressing HeLa cells are candidates for vascular protection.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130311"},"PeriodicalIF":2.5,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD28 and ICOS in immune regulation: Structural insights and therapeutic targeting","authors":"Saurabh Upadhyay,&nbsp;Baljit Kaur,&nbsp;Moustafa T. Gabr","doi":"10.1016/j.bmcl.2025.130310","DOIUrl":"10.1016/j.bmcl.2025.130310","url":null,"abstract":"<div><div>CD28 and ICOS are key immune checkpoints that regulate T-cell activation, differentiation, and immune tolerance. Their dysregulation contributes to cancer immune evasion, autoimmune diseases, and chronic inflammation, making them critical targets for therapeutic intervention. Recent advances in medicinal chemistry have led to the development of small-molecule inhibitors, monoclonal antibodies, and bispecific antibodies that selectively modulate CD28 and ICOS signaling. This review examines the structural and functional properties of CD28 and ICOS, highlighting their ligand-binding domains, intracellular signaling motifs, and structure-activity relationships (SARs) relevant to drug discovery. Key therapeutic approaches include CTLA-4-Ig fusion proteins (abatacept, belatacept) for autoimmune diseases, ICOS agonists (feladilimab, vopratelimab) to enhance anti-tumor immunity, and bispecific CD28-engaging antibodies (CD28xCD3, CD28xPSMA) for cancer immunotherapy. Additionally, novel high-throughput screening (HTS) strategies, computational drug design, and rational engineering of antibody-based therapies are improving selectivity and minimizing immune-related toxicities. By integrating structural insights with translational drug development, this review provides a framework for optimizing CD28- and ICOS-targeted therapies. Further advancements in biologics, peptide-based inhibitors, and immune checkpoint modulation will enhance the precision and efficacy of immunotherapeutic strategies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130310"},"PeriodicalIF":2.5,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and investigation of lipid-lowering and hepatoprotective effects of clofibrate-vanillin derivative based on structural optimization","authors":"Yumiao Song ,&nbsp;Xinyi Shi ,&nbsp;Xinyu Zhang ,&nbsp;Ling Ding ,&nbsp;Huizi Shangguan ,&nbsp;Xin Wang ,&nbsp;Jiping Liu ,&nbsp;Yongheng Shi ,&nbsp;Xinya Xu ,&nbsp;Yundong Xie","doi":"10.1016/j.bmcl.2025.130309","DOIUrl":"10.1016/j.bmcl.2025.130309","url":null,"abstract":"<div><div>The study aimed to optimize the structure of clofibrate to create a lipid-lowering medication with reduced liver damage properties. A new compound, clofibrate-vanillin (CF-Vanillin), was synthesized and tested in hyperlipidemic mice. The results showed that CF-Vanillin significantly reduce triglycerides (TG) and total cholesterol (TC), which was stronger than that of CF. The molecular docking results suggested that CF-Vanillin exhibits a favorable affinity towards PPAR-α. The results of the liver damage evaluation showed that CF-Vanillin significantly reduced liver damage compared to CF. The liver weight and liver coefficient of the CF-Vanillin group mice were significantly reduced (<em>P</em> <em>&lt;</em> 0.01). The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly reduced (<em>P</em> <em>&lt;</em> 0.05). Pathological analysis of liver tissue revealed a notable decrease in nuclear deformation, dissolution, inflammatory cell infiltration, and necrosis among mice treated with CF-Vanillin. Investigation into the liver damage reduction mechanism revealed a significant upregulation of Nrf2 and HO-1 expression (<em>P</em> <em>&lt;</em> 0.01) in the liver tissue of CF-Vanillin group mice. Furthermore, CF-Vanillin exhibited notable antioxidant and anti-inflammatory properties. The results imply that CF-Vanillin shows improved lipid-lowering effects and decreased liver damage possibly due to its antioxidant and anti-inflammatory actions by activating the Nrf2/HO-1 signaling pathway.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130309"},"PeriodicalIF":2.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a p21-activated kinase 1 (PAK1) inhibitor with 10-fold selectivity against PAK2","authors":"Deidre M. Johns ,&nbsp;Jason Olejniczak ,&nbsp;Anjali Babbar ,&nbsp;Christopher D. Boone ,&nbsp;Ozgur Cakici ,&nbsp;Melinda Cheng ,&nbsp;Qing-Qing Cheng ,&nbsp;Alexey Dementiev ,&nbsp;Mariam Eick ,&nbsp;Nicky Ferdyan ,&nbsp;Eric Fontano ,&nbsp;Aaron Forman ,&nbsp;Ryan Kozlowski ,&nbsp;Szu-Wei Lee ,&nbsp;Shital Mehta ,&nbsp;Kayla Mowery ,&nbsp;Brion Murray ,&nbsp;Vivian Nguyen ,&nbsp;Andrea Olland ,&nbsp;Kim B. Phan ,&nbsp;Siegfried Reich","doi":"10.1016/j.bmcl.2025.130307","DOIUrl":"10.1016/j.bmcl.2025.130307","url":null,"abstract":"<div><div>The p21-activated kinases (PAKs) are noted for their role in cytoskeletal organization, cellular morphogenesis, and pro-survival signaling. PAK1 is of particular interest due to its role in tumorigenesis, being amplified in multiple cancers (the most prevalent being breast, ovarian, and melanoma cancers). PAK2 is closely related to PAK1 in structure but is associated with cardiotoxicity. A structure-based design effort targeting a PAK1 (over PAK2) selective small molecule inhibitor is detailed herein. We report here the first crystal structure of PAK2 and use this crystal structure to design a PAK1 inhibitor with ten-fold selectivity over PAK2.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130307"},"PeriodicalIF":2.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}