Pub Date : 2026-02-03DOI: 10.1016/j.ejmech.2026.118644
Su Yu, Shichuan Hu, Weilin Wang, Chuntao Pan, Hongjia Zhang, Cong Zhou, Yang Liu, Rui Li
PROTACs offer a novel therapeutic strategy for addressing diseases driven by aberrant expression of pathogenic proteins. In this study, we identified a series of PROTAC molecules capable of degrading BRD2, BRD3, and BRD4. Structure–activity relationship analysis led to the discovery of CR10, a highly potent degrader that exhibited remarkable activity in MV4-11 cells. Mechanistic studies demonstrated that CR10 induced sustained degradation of target proteins via the ubiquitin–proteasome system. In mice models, intraperitoneal administration at 20 mg/kg achieved an exceptional bioavailability of 108.27%. Furthermore, CR10 significantly inhibited the growth of MV4-11 and A549 xenograft tumors at a dose as low as 2 mg/kg, without apparent toxicity. This semi-rigid linker–containing degrader represented a promising new mechanism-based candidate for the treatment of hematologic malignancies and lung cancer, warranting further investigation.
{"title":"Semi-Rigid Linkers Improve the Pharmacokinetic Properties and Therapeutic Efficacy of BET PROTACs for Cancer Therapy","authors":"Su Yu, Shichuan Hu, Weilin Wang, Chuntao Pan, Hongjia Zhang, Cong Zhou, Yang Liu, Rui Li","doi":"10.1016/j.ejmech.2026.118644","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118644","url":null,"abstract":"PROTACs offer a novel therapeutic strategy for addressing diseases driven by aberrant expression of pathogenic proteins. In this study, we identified a series of PROTAC molecules capable of degrading BRD2, BRD3, and BRD4. Structure–activity relationship analysis led to the discovery of <strong>CR10</strong>, a highly potent degrader that exhibited remarkable activity in MV4-11 cells. Mechanistic studies demonstrated that <strong>CR10</strong> induced sustained degradation of target proteins <em>via</em> the ubiquitin–proteasome system. In mice models, intraperitoneal administration at 20 mg/kg achieved an exceptional bioavailability of 108.27%. Furthermore, <strong>CR10</strong> significantly inhibited the growth of MV4-11 and A549 xenograft tumors at a dose as low as 2 mg/kg, without apparent toxicity. This semi-rigid linker–containing degrader represented a promising new mechanism-based candidate for the treatment of hematologic malignancies and lung cancer, warranting further investigation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"275 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1016/j.ejmech.2026.118612
Kevin C. Catalfano, Margaret H. Rakonick, Brian S.J. Blagg
Recent structure-activity relationship (SAR) studies identified multiple Hsp90/Aha1 small molecule disruptors that manifest moderately improved potencies and physiochemical properties. Among these molecules, a 1,5-bisubstituted-1,2,3-triazole containing molecule (Triazole A), demonstrated the importance of a cis-amide bond. Consequently, this work aimed to optimize Triazole A via a nitrogen scan and Topliss tree approach. The potency was determined against cell lysates and co-Immunoprecipitation (co-IP) experiments. The most efficacious molecules were evaluated for physiochemical properties that include aqueous solubility, human liver microsome half-life, and MDCK-MDR1 permeability. New molecules emerged from this study that manifest nanomolar potency and improved activity in cell-based co-IP experiments. These new molecules represent a significant improvement over prior Hsp90/Aha1 disruptors and provide chemical tools to investigate the significance of Hsp90/Aha1 complexes.
{"title":"Optimization of triazole-based small molecule disruptors of the Aha1/Hsp90 complex that manifest potent activities","authors":"Kevin C. Catalfano, Margaret H. Rakonick, Brian S.J. Blagg","doi":"10.1016/j.ejmech.2026.118612","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118612","url":null,"abstract":"Recent structure-activity relationship (SAR) studies identified multiple Hsp90/Aha1 small molecule disruptors that manifest moderately improved potencies and physiochemical properties. Among these molecules, a 1,5-bisubstituted-1,2,3-triazole containing molecule (Triazole A), demonstrated the importance of a <em>cis</em>-amide bond. Consequently, this work aimed to optimize Triazole A via a nitrogen scan and Topliss tree approach. The potency was determined against cell lysates and co-Immunoprecipitation (co-IP) experiments. The most efficacious molecules were evaluated for physiochemical properties that include aqueous solubility, human liver microsome half-life, and MDCK-MDR1 permeability. New molecules emerged from this study that manifest nanomolar potency and improved activity in cell-based co-IP experiments. These new molecules represent a significant improvement over prior Hsp90/Aha1 disruptors and provide chemical tools to investigate the significance of Hsp90/Aha1 complexes.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"61 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-31DOI: 10.1016/j.ejmech.2026.118613
Ashis Dhara, Eoin Hever, Fredrik Sjövall, Hakon Leffler, Ciaran O’Malley, Ulf J. Nilsson, Paul V. Murphy
{"title":"Synthesis of β-d-C-Galactopyranosyl Compounds Including Constrained Derivatives from Clickable Building Blocks and Evaluation as Ligands for Galectins","authors":"Ashis Dhara, Eoin Hever, Fredrik Sjövall, Hakon Leffler, Ciaran O’Malley, Ulf J. Nilsson, Paul V. Murphy","doi":"10.1016/j.ejmech.2026.118613","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118613","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-31DOI: 10.1016/j.ejmech.2026.118633
Jing Ye, Daihan Wang, Haiying Pang, Qiao Liu, Zhaoping Pan, Lian Wang, Bo Liu, Gu He
{"title":"Discovery of indolinone-based covalent ULK1 inhibitors that suppressed autophagy and induced apoptosis against colorectal carcinoma","authors":"Jing Ye, Daihan Wang, Haiying Pang, Qiao Liu, Zhaoping Pan, Lian Wang, Bo Liu, Gu He","doi":"10.1016/j.ejmech.2026.118633","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118633","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"93 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-30DOI: 10.1016/j.ejmech.2026.118622
Andrew M. Thompson, Nils-Jørgen K. Dal, Francesca Boldrin, Noelia Alonso-Rodriguez, Gabriela Schäfer, Kerstin Johann, Martin Speth, Laura Cioetto-Mazzabò, Adrián Pál, Jana Korduláková, Matthias Barz, Federico Fenaroli, William A. Denny, Gareth Griffiths
{"title":"New Antitubercular Pretomanid Analogues as Potent Payloads in Polymeric Micelles: Leveraging Zebrafish Assays to Accelerate Lead Optimisation","authors":"Andrew M. Thompson, Nils-Jørgen K. Dal, Francesca Boldrin, Noelia Alonso-Rodriguez, Gabriela Schäfer, Kerstin Johann, Martin Speth, Laura Cioetto-Mazzabò, Adrián Pál, Jana Korduláková, Matthias Barz, Federico Fenaroli, William A. Denny, Gareth Griffiths","doi":"10.1016/j.ejmech.2026.118622","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118622","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1016/j.ejmech.2026.118625
Fengxian Luo, Yanqing Pang, Yingjie Wang, Yanan Wang, Jun Yan, Lei Zhou
{"title":"Synthesis, Biological evaluation and Mechanism study of 2-benzoyl-quinazolinone derivative as ferroptosis inhibitor for the treatment of Parkinson’s disease","authors":"Fengxian Luo, Yanqing Pang, Yingjie Wang, Yanan Wang, Jun Yan, Lei Zhou","doi":"10.1016/j.ejmech.2026.118625","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118625","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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