Discovery of dual PARP/NAMPT inhibitors for the treatment of BRCA wild-type triple-negative breast cancer.

Simultaneous inhibition of poly(ADP-ribose) polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) has been shown to be synergistically effective against breast cancer susceptibility (BRCA) wild-type triple-negative breast cancer (TNBC) through synthetic lethality, which may be explored to broaden the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/NAMPT inhibitors through a pharmacophore linking approach. The lead compound 13j with potent inhibitory activity against both PARP1 and NAMPT (IC = 0.8 and 18 nM, respectively) effectively inhibited the proliferation of TNBC MDA-MB-231 cells with wild-type BRCA at submicromolar level. Mechanically, 13j disrupted the homologous recombination repair (HRR) pathway, caused the accumulation of DNA double-strand breaks (DSBs) and ultimately induced apoptotic cell death. In addition, this compound exhibited potent inhibitory potency on the migration of MDA-MB-231 cells. This study demonstrates that compound 13j is a promising lead compound for the development of better PARP/NAMPT inhibitors to treat TNBC with wild-type BRCA.