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

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.

Conclusion: These results indicated that our design compounds can serve as potent PI3Kα and BRAF dual inhibitors and effective antiproliferative agents, which can be further optimized to discover more potent PI3Kα and BRAF dual inhibitors.