Discovery of 10 H -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 and systematic structure-activity relationship (SAR) exploration, we discovered 10-benzo[]pyrido[2,3-][1,4]oxazine as a potent and orally bioavailable AXL inhibitor. As a type II AXL inhibitor, compound 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, exhibited significant antitumor efficacy in AXL-driven xenograft model at a well-tolerant dosage, causing tumor stasis or regression.