Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGF?R1 Inhibitor as an Immuno-oncology Agent.

ABSTRACT: Novel imidazole-based TGF?R1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGF?R1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGF?-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGF?R1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

SUBMITTER: Velaparthi U 

PROVIDER: S-EPMC7025382 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature