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
Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India.
ACS Med Chem Lett. 2020 Jan 28;11(2):172-178. doi: 10.1021/acsmedchemlett.9b00552. eCollection 2020 Feb 13.
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, (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative 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.
新型咪唑基TGFβR1抑制剂已被鉴定出来，并针对效力、选择性、药代动力学和物理化学特性进行了优化。在此，我们报告了一种强效、选择性且口服生物可利用的TGFβR1抑制剂（BMS-986260）的发现、优化及评估。该化合物在多种TGFβ依赖性细胞试验中表现出功能活性，具有出色的激酶组选择性、良好的药代动力学特性，并且在小鼠结直肠癌（CRC）模型中与抗PD-1抗体联合使用时具有治疗效果。由于已知在临床前物种中每日给药TGFβR1抑制剂会导致基于类别的心血管（CV）毒性，因此在抗PD-1联合疗效研究中探索了给药假期方案。在为期一个月的犬类和大鼠毒理学研究中，采用3天给药、4天停药的间歇给药方案可减轻CV毒性，并且其疗效与每日给药相似。
