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

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 mu-tations. 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 & mu;M), MDA-MB-468 (IC50 = 2.81 & mu;M) and BT-549 (IC50 = 2.37 & mu;M) 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.

Automated summary

Inhibition of PARP is effective targeted therapy for BRCA mutation type of TNBC patients. CDK4/6 inhibitors can increase sensitivity of wild-type BRCA cells to PARP inhibitors. The designed dual PARP and CDK6 inhibitor, P4i, showed good inhibitory activity against PARP1 and CDK6 and effective inhibition on MDA-MB-231, MDA-MB-468 and BT-549 cells with wild-type BRCA.