Discovery of dual PARP and CDK6 inhibitors for triple-negative breast cancer with wild-type BRCA

Abstract

Inhibition of PARP is synthetic lethal with defects in BRCA, which provide effective targeted therapy strategy for BRCA mutation type of TNBC patients. However, approximately 80% of TNBC patients do not have BRCA mutations. Recent studies have shown that CDK4/6 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and CDK6 inhibitors, and the most promising compound, P4i, showed good inhibitory activity against PARP1 and CDK6 and good inhibitory effects on MDA-MB-231 (IC₅₀ = 1.96 μM), MDA-MB-468 (IC₅₀ = 2.81 μM) and BT-549 (IC₅₀ = 2.37 μM) cells with wild-type BRCA. Compared with Olaparib, the inhibition capacity of the three BRCA wild-type (MDA-MB-231, MDA-MB-468 and BT-549) cells was about 10-20 times higher, and even better than the combination of Olaparib and Palbociclib. As a novel PARP multifunctional molecule, it is a potential compound for the treatment of BRCA wild-type TNBC.

Keywords: Breast cancer susceptibility gene 1/2; Cyclin-dependent kinases 6; Poly(ADP-ribose) polymerase; Synthetic lethality; Triple-Negative Breast Cancer.