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 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.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Isocitrate Dehydrogenase/antagonists & inhibitors , Quinolones/chemistry , Quinolones/pharmacology , Allosteric Site/drug effects , Animals , Biological Availability , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Drug Discovery , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Isocitrate Dehydrogenase/chemistry , Isocitrate Dehydrogenase/genetics , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Models, Molecular , Point Mutation , Quinolones/pharmacokineticsABSTRACT
The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models.
