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.

中文翻译：

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发现了BMS-986260，这是一种有效，选择性和口服生物利用的TGFβR1抑制剂，可作为免疫肿瘤药。

鉴定了基于咪唑的新型TGFβR1抑制剂，并对其效价，选择性以及药代动力学和理化特性进行了优化。本文中，我们报告了一种有效的，选择性的和口服生物利用的TGFβR1抑制剂10（BMS-986260）的发现，优化和评估。在鼠大肠癌（CRC）模型中，该化合物在多种TGFβ依赖性细胞试验中具有功能活性，优异的激酶组选择性，良好的药代动力学特性以及与抗PD-1抗体结合的治愈性体内疗效。由于已知每天服用TGFβR1抑制剂会在临床前物种中引起基于类别的心血管（CV）毒性，因此在抗PD-1联合功效研究中探索了给药假期时间表。