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

  • ACS Med Chem Lett. 2020 Jan 28;11(2):172-178. doi: 10.1021/acsmedchemlett.9b00552.
Upender Velaparthi  1 ,  Chetan Padmakar Darne  1 ,  Jayakumar Warrier  2 ,  Peiying Liu  1 ,  Hasibur Rahaman  2 ,  Karen Augustine-Rauch  1 ,  Karen Parrish  1 ,  Zheng Yang  1 ,  Jesse Swanson  1 ,  Jennifer Brown  1 ,  Gopal Dhar  2 ,  Aravind Anandam  2 ,  Vinay K Holenarsipur  2 ,  Kamalavenkatesh Palanisamy  2 ,  Barri S Wautlet  1 ,  Mark P Fereshteh  1 ,  Jonathan Lippy  1 ,  Andrew J Tebben  1 ,  Steven Sheriff  1 ,  Max Ruzanov  1 ,  Chunhong Yan  1 ,  Anuradha Gupta  2 ,  Arun Kumar Gupta  2 ,  Muthalagu Vetrichelvan  2 ,  Arvind Mathur  1 ,  Marina Gelman  3 ,  Rajinder Singh  3 ,  Todd Kinsella  3 ,  Anwar Murtaza  1 ,  Joseph Fargnoli  1 ,  Gregory Vite  1 ,  Robert M Borzilleri  1
Affiliations
  • 1. Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 2. Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India.
  • 3. Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 32071685 DOI: 10.1021/acsmedchemlett.9b00552
Abstract

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.

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