Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy

Abstract

Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC₅₀ values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.