Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors
| Autor: | K.J. Barr, A. Ericsson, Zhongguo Wang, David R. Lancia, A. Clarke, R.B. Diebold, S. Ashwell, George P. Luke, Deepali Gotur, Wei Lu, Jian Lin, H.R. Josephine, M. Katz, D. Walker, A.M. Campbell, Goss Stryker Kauffman, L. Yao, Angela V. Toms, Caravella Justin Andrew, H. Diep, Jennifer Castro, Kenneth W. Bair, E. Fritzen, Christopher J. Dinsmore, Stephen Hubbs, Le Wang, G.R. Gustafson, Tatiana E. Shelekhin, Mark T. Kershaw |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular IDH1 Allosteric regulation Biological Availability Pharmacology Quinolones Crystallography X-Ray 01 natural sciences Madin Darby Canine Kidney Cells 03 medical and health sciences Mice Dogs Cell Line Tumor Drug Discovery Animals Humans Point Mutation Enzyme Inhibitors 030304 developmental biology ADME 0303 health sciences Mice Inbred BALB C Chemistry Drug discovery Myeloid leukemia Oxidoreductase inhibitor Small molecule Isocitrate Dehydrogenase 0104 chemical sciences 010404 medicinal & biomolecular chemistry Isocitrate dehydrogenase Molecular Medicine Female Allosteric Site |
| Zdroj: | Journal of medicinal chemistry. 62(14) |
| ISSN: | 1520-4804 |
| Popis: | 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 24 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 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials. |
| Databáze: | OpenAIRE |
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