Structural Optimization of Pyrazole Compounds as Hsp90 Regulators with Enhanced Antitumor Activity

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-05-01 DOI:10.1021/acs.jmedchem.4c02182

Zi-Wen Feng, Li Li, Shi-Duo Zhang, Ying-Ji Wang, Jia-Yue Pei, Nan-Nan Chen, Bei-Duo Wu, Qiu-Ling Zheng, Qi-Dong You, Xiao-Ke Guo, Xiao-Li Xu

{"title":"Structural Optimization of Pyrazole Compounds as Hsp90 Regulators with Enhanced Antitumor Activity","authors":"Zi-Wen Feng, Li Li, Shi-Duo Zhang, Ying-Ji Wang, Jia-Yue Pei, Nan-Nan Chen, Bei-Duo Wu, Qiu-Ling Zheng, Qi-Dong You, Xiao-Ke Guo, Xiao-Li Xu","doi":"10.1021/acs.jmedchem.4c02182","DOIUrl":null,"url":null,"abstract":"Targeting Hsp90 is an effective strategy for cancer therapy. TAS-116 has been approved for the treatment of gastrointestinal stromal tumors. Our previous studies identified a series of pyrazole derivatives as covalent Hsp90 inhibitors that allosterically disrupt the Hsp90-Cdc37 interaction. Here, through systematic structure–activity relationship (SAR) optimization, compound 39 (DDO-6691) with a new covalent warhead was developed, which demonstrates improved ADME properties and significantly enhanced antitumor activity. Notably, parental HCT-116 cells exhibited markedly greater sensitivity to compound 39 (IC50 > 50 μM) compared to their Cdc37-knockout counterparts. Importantly, compound 39 displayed potent tumor growth inhibition in HCT-116 xenograft mouse models. These collective findings underscore the therapeutic promise of covalent Hsp90-targeted disruption of the Hsp90-Cdc37 complex, offering a novel mechanistic approach to cancer treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"56 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c02182","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Targeting Hsp90 is an effective strategy for cancer therapy. TAS-116 has been approved for the treatment of gastrointestinal stromal tumors. Our previous studies identified a series of pyrazole derivatives as covalent Hsp90 inhibitors that allosterically disrupt the Hsp90-Cdc37 interaction. Here, through systematic structure–activity relationship (SAR) optimization, compound 39 (DDO-6691) with a new covalent warhead was developed, which demonstrates improved ADME properties and significantly enhanced antitumor activity. Notably, parental HCT-116 cells exhibited markedly greater sensitivity to compound 39 (IC₅₀ > 50 μM) compared to their Cdc37-knockout counterparts. Importantly, compound 39 displayed potent tumor growth inhibition in HCT-116 xenograft mouse models. These collective findings underscore the therapeutic promise of covalent Hsp90-targeted disruption of the Hsp90-Cdc37 complex, offering a novel mechanistic approach to cancer treatment.

Abstract Image

查看原文本刊更多论文

吡唑类抗肿瘤Hsp90调节剂的结构优化

靶向Hsp90是癌症治疗的有效策略。TAS-116已被批准用于胃肠道间质瘤的治疗。我们之前的研究确定了一系列吡唑衍生物作为共价Hsp90抑制剂，它们变构破坏Hsp90- cdc37的相互作用。本文通过系统构效关系（SAR）优化，开发出具有新型共价战斗部的化合物39 (do -6691)，其ADME性能得到改善，抗肿瘤活性显著增强。值得注意的是，亲代HCT-116细胞对化合物39 (IC50 >；50 μM)，与敲除cdc37的细胞相比。重要的是，化合物39在HCT-116异种移植小鼠模型中显示出有效的肿瘤生长抑制作用。这些集体发现强调了共价hsp90靶向破坏Hsp90-Cdc37复合物的治疗前景，为癌症治疗提供了一种新的机制方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.