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

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.

Copper‐Catalyzed Regioselective Halogenation of Anilides with N‐Fluorobenzenesulfonimide

“…N ‐(4‐chloro‐3‐methoxyphenyl)acetamide 2 j : [23] white solid (12.8 mg, 32 %); R f =0.2 (petroleum ether/ethyl acetate=5 : 1); 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J =2.7 Hz, 1H), 7.61 (br, 1H), 7.23 (d, J =8.9 Hz, 1H), 6.60 (dd, J =8.9, 2.8 Hz, 1H), 3.81 (s, 3H), 2.24 (s, 3H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 168.5, 154.2, 134.1, 129.3, 117.2, 113.2, 104.9, 56.4, 25.0; MS (C 9 H 10 ClNO 2 ): 200 [M+1] + .…”

A Review of the Recent Developments of Molecular Hybrids Targeting Tubulin Polymerization

“…Heterocycle-fused quinolinone is another privileged structure used as a building block in drug discovery. The quinolinone hybrids have shown biological activities, including antimicrobial [ 75 ], anti-inflammatory [ 76 ], anticancer [ 77 ], anti-Alzheimer [ 78 ], and anti-leishmanial [ 79 ] effects. Interestingly, quinolinone derivatives can successfully inhibit IDH1 mutants R132H, R132C, R132G, and R132L and display good selectivity vs. the wild-type IDH protein [ 80 ].…”

Application of Chiral Sulfinamides into Formation and Reduction of Sulfinylketimines to Obtain Valuable α‐Chiral Primary Amines

“…The same year, Lin, Dinsmore et al synthesized a wide range of mutant isocitrate dehydrogenase 1 inhibitors . Six of these molecules were synthesized using the condensation – reduction process as described in Scheme .…”