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. 2025 Jul 1:122:130190.
doi: 10.1016/j.bmcl.2025.130190. Epub 2025 Mar 17.

Discovery of ATP competitive PDHK1/2 dual inhibitors

Hongtao Xu  1 , Dong Ding  1 , Xingchun Han  1 , Kun Miao  1 , Chungen Liang  1 , Hongying Yun  1 , Wei Zhu  1 , Fabian Dey  2 , Dan Zhao  1 , Yao Wu  1 , Michael Reutlinger  2 , June Yang  1 , Guanglei Zhai  1 , Zhaohu Lin  1 , Chiho Li  1 , Waikong Wu  1 , Bruce Xu  1 , Li Han  1 , Shuai Chen  1 , Xinyi Huang  1 , Fabio Casagrande  2 , Manuel Hilbert  2 , Quentin Strebel  2 , Moreno Wichert  2 , Paul Westwood  2 , Ramona Schäfer  2 , Doris Roth  2 , Dominik Heer  2 , Xiaojun Tian  1 , Tiantian Ma  1 , Tong Zhang  1 , Jie Zhao  1 , Eduard Urich  1 , Guliang Xia  1 , Kara Lassen  2 , Hong C Shen  1 , Ge Zou  3
Affiliations

Discovery of ATP competitive PDHK1/2 dual inhibitors

Hongtao Xu et al. Bioorg Med Chem Lett. .

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.

Keywords: Covalent inhibitor; Kinase inhibitors for immunometabolism; Structure based design.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The majority of the authors are currently employed by Roche and may hold shares in the company. This affiliation may present a potential conflict of interest. However, we affirm that the research was conducted with the highest standards of scientific integrity and objectivity. The findings and conclusions presented in this manuscript are solely based on the data and analysis performed during the study.

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