Tropomyosin receptor kinase (TRK) fusion, an oncogenic form of kinase with pan-tumor occurrence, is a clinically validated important antitumor target. In this study, we screened our in-house kinase inhibitor library against TRK and identified a promising hit compound 4 with a novel pyridin-2(1H)-one scaffold. Through a combination of structure-based drug design and structure–activity relationship (SAR) study, compound 14q was identified as a potent TRK inhibitor with good kinase selectivity. It also blocked cellular TRK signaling, thereby inhibiting TRK-dependent cell viability. Additionally, 14q displayed acceptable pharmacokinetic properties with 37.8% oral bioavailability in mice. Strong in vivo tumor growth inhibition of 14q was observed in subcutaneous M091 and KM12 tumor xenograft models with TRK fusion, causing significant tumor inhibition or even complete tumor regression.

中文翻译：

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新型 Pyridin-2(1H)-one 类似物作为有效 TRK 抑制剂用于癌症治疗的发现、优化和评估

原肌球蛋白受体激酶 (TRK) 融合是一种具有泛肿瘤发生的致癌形式激酶，是经过临床验证的重要抗肿瘤靶点。在这项研究中，我们筛选了针对 TRK 的内部激酶抑制剂库，并鉴定了一种具有新型吡啶-2(1 H )-one 支架的有前途的热门化合物4。通过结合基于结构的药物设计和构效关系（SAR）研究，化合物14q被确定为一种有效的TRK抑制剂，具有良好的激酶选择性。它还阻断细胞 TRK 信号传导，从而抑制 TRK 依赖性细胞活力。此外，14q在小鼠中显示出可接受的药代动力学特性，口服生物利用度为 37.8%。在TRK融合的皮下M091和KM12肿瘤异种移植模型中观察到对14q的体内肿瘤生长的强烈抑制，导致显着的肿瘤抑制甚至肿瘤完全消退。