6O2Y

Crystal structure of IDH1 R132H mutant in complex with compound 24

6O2Y の概要

• エントリーDOI: 10.2210/pdb6o2y/pdb
• 分子名称: Isocitrate dehydrogenase [NADP] cytoplasmic, 4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: idh1, allosteric inhibitor, oxidoreductase, inhibitor complex, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 147860.83

構造登録者

Toms, A.V.,Lin, J. (登録日: 2019-02-25, 公開日: 2019-06-26, 最終更新日: 2024-03-13)

主引用文献

Lin, J.,Lu, W.,Caravella, J.A.,Campbell, A.M.,Diebold, R.B.,Ericsson, A.,Fritzen, E.,Gustafson, G.R.,Lancia Jr., D.R.,Shelekhin, T.,Wang, Z.,Castro, J.,Clarke, A.,Gotur, D.,Josephine, H.R.,Katz, M.,Diep, H.,Kershaw, M.,Yao, L.,Kauffman, G.,Hubbs, S.E.,Luke, G.P.,Toms, A.V.,Wang, L.,Bair, K.W.,Barr, K.J.,Dinsmore, C.,Walker, D.,Ashwell, S.
Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.
J.Med.Chem., 62:6575-6596, 2019

PubMed Abstract: Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of yielded a preclinical candidate . The detailed preclinical ADME and pharmacology studies of support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.

PubMed: 31199148
DOI: 10.1021/acs.jmedchem.9b00362

実験手法

X-RAY DIFFRACTION (2.8 Å)