Design, Synthesis, and Biological Evaluation of Novel Phosphoinositide 3-Kinase (PI3K) α Inhibitors toward Cancer Treatment.

The phosphoinositide 3-kinase (PI3K) is an essential factor in tumor development and has been viewed as a very effective potential target. Based on the study of PI3K's structure and functions, we designed and synthesized a series of novel PI3K inhibitors with a 2,4-dimorpholino-1,3,5-triazine scaffold incorporating an NO donor module, and evaluated their antiproliferative effects on 4T1, A549, HeLa, HepG2, MCF-7, MDA-MB-231, and CT26 cells in vitro, as well as PI3Kα inhibitory activity. Among them, compound 5k demonstrated a strong antiproliferative activity on CT26 cells (IC50 = 10 nM) by inhibiting the PI3K pathway and releasing NO from the furoxan moiety to induce apoptosis. Moreover, compound 5k has been confirmed with significant anticancer efficacy according to the in vivo efficacy evaluation in an allograft mouse model. Overall, compound 5k is a promising PI3K inhibitor deserving further preclinical investigation for tumor treatment.