Hongtao Xu , Dong Ding , Xingchun Han , Kun Miao , Chungen Liang , Hongying Yun , Wei Zhu , Fabian Dey , Dan Zhao , Yao Wu , Michael Reutlinger , June Yang , Guanglei Zhai , Zhaohu Lin , Chiho Li , Waikong Wu , Bruce Xu , Li Han , Shuai Chen , Xinyi Huang , Ge Zou
{"title":"Discovery of ATP competitive PDHK1/2 dual inhibitors","authors":"Hongtao Xu , Dong Ding , Xingchun Han , Kun Miao , Chungen Liang , Hongying Yun , Wei Zhu , Fabian Dey , Dan Zhao , Yao Wu , Michael Reutlinger , June Yang , Guanglei Zhai , Zhaohu Lin , Chiho Li , Waikong Wu , Bruce Xu , Li Han , Shuai Chen , Xinyi Huang , Ge Zou","doi":"10.1016/j.bmcl.2025.130190","DOIUrl":null,"url":null,"abstract":"<div><div>Multiple screening approaches were carried out to identify novel chemistry starting for Pyruvate Dehydrogenase Kinases (PDHKs) inhibitors. Through hit triaging efforts and structure-based optimization, two series of ATP competitive inhibitors with single digit nanomolar enzymatic potency for PDHK1/2 and around 10–100-fold selectivity over PDHK4/3 were discovered. Approach of covalent inhibitor was explored to successfully improve the cellular target engagement to single digit micromolar range.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130190"},"PeriodicalIF":2.2000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X2500099X","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/17 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Multiple screening approaches were carried out to identify novel chemistry starting for Pyruvate Dehydrogenase Kinases (PDHKs) inhibitors. Through hit triaging efforts and structure-based optimization, two series of ATP competitive inhibitors with single digit nanomolar enzymatic potency for PDHK1/2 and around 10–100-fold selectivity over PDHK4/3 were discovered. Approach of covalent inhibitor was explored to successfully improve the cellular target engagement to single digit micromolar range.
期刊介绍：
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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