9M3O

Crystal structure of human pyruvate dehydrogenase kinase isoform 1 in complex with ATP competitive inhibitor 8

これはPDB形式変換不可エントリーです。

9M3O の概要

• エントリーDOI: 10.2210/pdb9m3o/pdb
• 分子名称: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial, POTASSIUM ION, 6-fluoranyl-8-(methylamino)-N-(pyrimidin-5-ylmethyl)-9H-pyrido[2,3-b]indole-3-carboxamide, ... (5 entities in total)
• 機能のキーワード: ghkl atpase/kinase family, pyruvate dehydrogenase complex, mitochondrial kinase, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44454.63

構造登録者

Xu, Z.H.,Chen, S. (登録日: 2025-03-03, 公開日: 2025-04-02)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.762 Å)