Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by property-driven optimization.

Abstract

Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 (10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC50\xa0=\xa056.4\xa0nM) against the KM12 human colorectal cancer cell line. 39 also displayed good AUC and oral bioavailability (F\xa0=\xa027%), excellent in\xa0vivo efficacy (TGI\xa0=\xa064%) in a KM12 xenograft model, and broad-spectrum anti-TRK mutant potency (IC50\xa0=\xa03.74-151.4\xa0nM), especially in the double-mutant TRKA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II TRK inhibitor.