Discovery of ATP competitive PDHK1/2 dual inhibitors

  • Bioorg Med Chem Lett. 2025 Jul 1:122:130190. doi: 10.1016/j.bmcl.2025.130190.
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
  • 1. China Innovation Center of Roche, No. 371 Lishizhen Road, Shanghai, 201203, China.
  • 2. Pharmaceutical Research and Early Development, F. Hoffmann-La Roche AG, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • 3. China Innovation Center of Roche, No. 371 Lishizhen Road, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 40107630 DOI: 10.1016/j.bmcl.2025.130190
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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