Receptor tyrosine kinase AXL exerts pivotal roles in cancer cell survival, metastasis, and drug resistance. Pharmacologic or genetic targeting of the aberrant AXL signaling has proven preferable antitumor efficacies in both preclinical and clinical studies, which highlights AXL as an attractive antitumor drug target. By conformational restriction of the anilinopyrimidine 10e and systematic structure–activity relationship (SAR) exploration, we discovered 10H-benzo[b]pyrido[2,3-e][1,4]oxazine 16j as a potent and orally bioavailable AXL inhibitor. As a type II AXL inhibitor, compound 16j displayed about 15-fold selectivity for AXL over its highly homologous kinase c-Met. And it significantly blocked cellular AXL signaling, inhibited AXL-mediated cell proliferation, and impaired growth arrest-specific protein 6 (Gas6)/AXL-stimulated cell migration and invasion. Moreover, 16j exhibited significant antitumor efficacy in AXL-driven xenograft model at a well-tolerant dosage, causing tumor stasis or regression.

中文翻译：

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通过基于结构的靶向 c-Met 激酶的药物设计发现 10H-苯并[b]吡啶并[2,3-e][1,4]恶嗪 AXL 抑制剂

受体酪氨酸激酶 AXL 在癌细胞存活、转移和耐药性中发挥关键作用。异常 AXL 信号的药理学或遗传靶向已在临床前和临床研究中证明具有更好的抗肿瘤功效，这突出了 AXL 作为有吸引力的抗肿瘤药物靶点。通过对苯胺基嘧啶10e的构象限制和系统构效关系 (SAR) 探索，我们发现 10 H -benzo[ b ]pyrido[2,3- e ][1,4]oxazine 16j作为一种有效的口服生物可利用的 AXL 抑制剂. 作为 II 型 AXL 抑制剂，化合物16j与其高度同源的激酶 c-Met 相比，AXL 显示出约 15 倍的选择性。它显着阻断细胞 AXL 信号传导，抑制 AXL 介导的细胞增殖，并损害生长停滞特异性蛋白 6 (Gas6)/AXL 刺激的细胞迁移和侵袭。此外，16j在 AXL 驱动的异种移植模型中以耐受性良好的剂量表现出显着的抗肿瘤功效，导致肿瘤停滞或消退。