1. Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent
- Author
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Jennifer Brown, Karen E. Parrish, Andrew J. Tebben, Jonathan Lippy, Kamalavenkatesh Palanisamy, Todd Kinsella, Chetan Padmakar Darne, Vinay K. Holenarsipur, Anwar Murtaza, Muthalagu Vetrichelvan, Chunhong Yan, Karen Augustine-Rauch, Max Ruzanov, Mark Fereshteh, Upender Velaparthi, Gopal Dhar, Gregory D. Vite, Peiying Liu, Steven Sheriff, Jayakumar Sankara Warrier, Aravind Anandam, Marina Gelman, Arvind Mathur, Barri Wautlet, Robert M. Borzilleri, Hasibur Rahaman, Zheng Yang, Anuradha Gupta, Arun Kumar Gupta, Rajinder Singh, Joseph Fargnoli, and Jesse Swanson
- Subjects
biology ,010405 organic chemistry ,business.industry ,Organic Chemistry ,Pharmacology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Bioavailability ,010404 medicinal & biomolecular chemistry ,Regimen ,Pharmacokinetics ,In vivo ,Drug Discovery ,biology.protein ,Medicine ,Potency ,Kinome ,Dosing ,Antibody ,business - Abstract
[Image: see text] Novel imidazole-based TGFβR1 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 TGFβR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-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 TGFβR1 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.
- Published
- 2020