1. Academic Validation
  2. Discovery of ATP competitive PDHK1/2 dual inhibitors

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

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: ge.zou@roche.com.
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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