Discovery of ATP competitive PDHK1/2 dual inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 122; pp. 130190 - 130196
• Main Authors: Xu, Hongtao, Ding, Dong, Han, Xingchun, Miao, Kun, Liang, Chungen, Yun, Hongying, Zhu, Wei, Dey, Fabian, Zhao, Dan, Wu, Yao, Reutlinger, Michael, Yang, June, Zhai, Guanglei, Lin, Zhaohu, Li, Chiho, Wu, Waikong, Xu, Bruce, Han, Li, Chen, Shuai, Huang, Xinyi, Casagrande, Fabio, Hilbert, Manuel, Strebel, Quentin, Wichert, Moreno, Westwood, Paul, Schäfer, Ramona, Roth, Doris, Heer, Dominik, Tian, Xiaojun, Ma, Tiantian, Zhang, Tong, Zhao, Jie, Urich, Eduard, Xia, Guliang, Lassen, Kara, Shen, Hong C., Zou, Ge
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.07.2025; Elsevier
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Covalent inhibitor; Dose-Response Relationship, Drug; Drug Discovery; Humans; Kinase inhibitors for immunometabolism; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Science & Technology; Structure based design; Structure-Activity Relationship; Structure based design; Covalent inhibitor; Kinase inhibitors for immunometabolism; PYRUVATE-DEHYDROGENASE; DEHYDROGENASE KINASE INHIBITORS
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2025.130190

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. [Display omitted] •Multiple ATP-competitive PDHK1 hits were identified through integrated screening approaches.•Structure-based design was utilized to further improve ligand efficiency and address the solubility issues of the most potent hit series.•Two novel series achieved potent enzymatic activity for PDHK1 and PDHK2 with selectivity over PDHK3/4.•Discovery and confirmation of the first Lys-covalent inhibitor of PDHK1.