Discovery of 2-(aminopyrimidin-5-yl)-4-(morpholin-4-yl)-6- substituted triazine as PI3K and BRAF dual inhibitor

摘要

Aim: The discovery and development of novel agents simultaneously targeting PI3K/AKT/mammalian target of rapamycin and Ras/RAF/MEK, two signaling pathways, are urgent to improve the curative effect of kinase inhibitors and overcome acquired resistance. Methods/results: In the present study, 2-(2-aminopyrimidin-5-yl)-4-(morpholin-4-yl)-6-( N -cyclopropyl- N - (1-benzoylpiperidin-4-yl))triazines/pyrimidines were designed as PI3K and BRAF dual inhibitors. The synthesized 20 compounds exhibited potent antiproliferative effects in vitro against HCT116, A375, MCF-7, Colo205, A549 and LOVO cancer cell lines. The tested compounds A6 , A7 , A9 and A11 remarkably displayed inhibitory activities toward both PI3Kα and BRAF~(V600E). Conclusion: These results indicated that our design compounds can serve as potent PI3Kα and BRAF~(V600E) dual inhibitors and effective antiproliferative agents, which can be further optimized to discover more potent PI3Kα and BRAF~(V600E) dual inhibitors.Graphical abstract2-(2-Aminopyrimidin-5-yl)-4-(morpholin-4-yl)-6-( N -cyclopropyl- N -(1-benzoylpiperid-ine-4-yl))triazines can act as PI3K and BRAF dual inhibitors.