Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent

• Published in: ACS medicinal chemistry letters 2020-02, Vol.11 (2), p.172-178
• Main Authors: Velaparthi, Upender, Darne, Chetan Padmakar, Warrier, Jayakumar, Liu, Peiying, Rahaman, Hasibur, Augustine-Rauch, Karen, Parrish, Karen, Yang, Zheng, Swanson, Jesse, Brown, Jennifer, Dhar, Gopal, Anandam, Aravind, Holenarsipur, Vinay K, Palanisamy, Kamalavenkatesh, Wautlet, Barri S, Fereshteh, Mark P, Lippy, Jonathan, Tebben, Andrew J, Sheriff, Steven, Ruzanov, Max, Yan, Chunhong, Gupta, Anuradha, Gupta, Arun Kumar, Vetrichelvan, Muthalagu, Mathur, Arvind, Gelman, Marina, Singh, Rajinder, Kinsella, Todd, Murtaza, Anwar, Fargnoli, Joseph, Vite, Gregory, Borzilleri, Robert M
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.9b00552

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.