6O2Z
Crystal structure of IDH1 R132H mutant in complex with compound 32
Summary for 6O2Z
| Entry DOI | 10.2210/pdb6o2z/pdb |
| Descriptor | Isocitrate dehydrogenase [NADP] cytoplasmic, 6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methylpyridine-3-carbonitrile, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total) |
| Functional Keywords | idh1, allosteric inhibitor, oxidoreductase, inhibitor complex, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 98591.89 |
| Authors | Toms, A.V.,Lin, J. (deposition date: 2019-02-25, release date: 2019-06-26, Last modification date: 2024-03-13) |
| Primary citation | 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 Cited by 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: 31199148DOI: 10.1021/acs.jmedchem.9b00362 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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