2. Academic Validation
  3. Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent

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

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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