气体6
化学
AXL受体酪氨酸激酶
受体酪氨酸激酶
药理学
细胞生长
激酶
酪氨酸激酶
酪氨酸激酶抑制剂
药品
癌症研究
转移
癌症
受体
生物化学
生物
内科学
医学
JAK-STAT信号通路
作者
Zhengsheng Zhan,Yinchun Ji,Haixia Su,Fang Chen,Peng Xia,Qiufeng Liu,Yang Dai,Dong-Ze Lin,Yechun Xu,Jing Ai,Wenhu Duan
标识
DOI:10.1021/acs.jmedchem.2c00962
摘要
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.
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