Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors

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.