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

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 15 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 15 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, 15 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 15, a
first potent dual PARP/PI3K inhibitor, is a highly effective anticancer
compound.