Discovery of 10H‑Benzo[b]pyrido[2,3‑e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c‑Met Kinase

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.

受体酪氨酸激酶AXL（Receptor tyrosine kinase AXL）在癌细胞存活、转移及耐药性形成过程中发挥关键作用。临床前与临床研究均证实，对异常AXL信号通路实施药理学或遗传学靶向干预，可获得优异的抗肿瘤疗效，这进一步凸显AXL是极具吸引力的抗肿瘤药物靶点。本研究通过对苯胺并嘧啶10e进行构象限制，并开展系统性构效关系（SAR）探索，成功发现10H-苯并[b]吡啶并[2,3-e][1,4]噁嗪16j是一种强效且口服生物可利用的AXL抑制剂。作为II型AXL抑制剂，化合物16j对AXL的选择性约为其高度同源激酶c-Met的15倍。该化合物可显著阻断细胞内AXL信号通路，抑制AXL介导的细胞增殖，并削弱生长停滞特异性蛋白6（Gas6）/AXL通路激活的细胞迁移与侵袭能力。此外，在耐受良好的给药剂量下，16j在AXL驱动的异种移植模型中展现出显著的抗肿瘤疗效，可实现肿瘤生长停滞或消退。