Design and synthesis of novel imidazopyridine derivatives as potent PI3K inhibitors with anticancer activity

Abstract

Phosphatidylinositol 3-kinase alpha (PI3Kα) is an important regulator of intracellular signaling pathway controlling various cellular functions such as cell growth, proliferation, differentiation, and survival. Since PI3K pathway is frequently up-regulated in human cancers, the inhibition of PI3Kα can be a promising approach to the cancer treatment. In studies toward identifying effective inhibitors of PI3K signaling cascade, we have designed and synthesized a series of imidazo[1,2-a]pyridine derivatives as PI3Kα inhibitors, guided by docking modeling. Herein, we explain our studies on the structure-activity relationship (SAR) at the variation of C3 and C6 positions of imidazo[1,2-a]pyridine scaffold, and illustrate the biological evaluation in antiproliferative and antiangiogenic activities on various cancer cell lines. Especially, N-(5-(3-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide was identified as a highly potent PI3Kα inhibitor with an IC50 of 2 nM and good pharmacokinetic (PK) parameters and exhibited strong antiangiogenic effect on Huh-7 human hepatocarcinoma cells.