Chimeric Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP1) and Nicotinamide Phosphoribosyltransferase (NAMPT) for Cancer Therapy

Combining inhibition of both (poly[ADP-ribose] polymerase-1) PARP1 and nicotinamide phosphoribosyltransferase (NAMPT) is a mechanistically synergistic strategy to exploit the dependence on NAD⁺ for DNA repair and survival of cancer cells under genotoxic or metabolic stress. Many cancer cells overexpress NAMPT to maintain high NAD⁺ levels, supporting glycolysis, oxidative phosphorylation, and DNA repair. PARP1 inhibition is clinically successful in ovarian cancer and more modestly in other cancers, such as triple negative breast cancer (TNBC); whereas NAMPT inhibitors have not shown convinc-ing clinical risk/benefit ratio in trials. Chimeric inhibitors of both PARP and NAMPT (XPN) were readily obtained incorporat-ing dual “warheads” that bind to the nicotinamide (NAM) binding site in PARP and NAMPT. XPN potency in cell-based and cell-free bioassays was nanomolar, or below, and selectivity of almost 100-fold was achieved for PARP1 over PARP2 inhibi-tion. Oral bioavailability of XPN tested was at least tenfold greater than potency observed in cell cultures. Antiproliferative potency in TNBC cells correlated with potency for reduction of cellular NAD+ levels in TNBC cells.