Discovery of 2-(aminopyrimidin-5-yl)-4-(morpholin-4-yl)-6- Substituted Triazine as PI3K and BRAF Dual Inhibitor

Abstract

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.

Plain Language Summary

Graphical abstract 2-(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.

Keywords: :

• antiproliferative effects
• BRAF inhibitor
• drug design
• PI3K and BRAF dual inhibitor
• PI3K inhibitor

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Financial & competing interests disclosure

Financial support from National Natural Science Foundation of China (81402792) is gratefully acknowledged. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.