9M3U

Crystal structure of human pyruvate dehydrogenase kinase isoform 2 in complex with ATP competitive inhibitor 24

This is a non-PDB format compatible entry.

Summary for 9M3U

• Entry DOI: 10.2210/pdb9m3u/pdb
• Descriptor: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial, 1,2-ETHANEDIOL, N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL} ACETAMIDE, ... (6 entities in total)
• Functional Keywords: ghkl atpase/kinase family, pyruvate dehydrogenase complex, mitochondrial kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 42175.62

Authors

Xu, Z.H.,Chen, S.,Han, L. (deposition date: 2025-03-03, release date: 2025-06-25)

Primary citation

Xu, H.,Ding, D.,Han, X.,Miao, K.,Liang, C.,Yun, H.,Zhu, W.,Dey, F.,Zhao, D.,Wu, Y.,Reutlinger, M.,Yang, J.,Zhai, G.,Lin, Z.,Li, C.,Wu, W.,Xu, B.,Han, L.,Chen, S.,Huang, X.,Casagrande, F.,Hilbert, M.,Strebel, Q.,Wichert, M.,Westwood, P.,Schafer, R.,Roth, D.,Heer, D.,Tian, X.,Ma, T.,Zhang, T.,Zhao, J.,Urich, E.,Xia, G.,Lassen, K.,Shen, H.C.,Zou, G.
Discovery of ATP competitive PDHK1/2 dual inhibitors.
Bioorg.Med.Chem.Lett., 122:130190-130190, 2025

PubMed 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.

PubMed: 40107630
DOI: 10.1016/j.bmcl.2025.130190

Experimental method

X-RAY DIFFRACTION (1.92 Å)