Discovery of Highly Potent Nicotinamide Phosphoribosyltransferase Degraders for Efficient Treatment of Ovarian Cancer
Kaijian Bi, Junfei Cheng, Shipeng He, Yuxin Fang, Min Huang, Chunquan Sheng, Guoqiang Dong
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is identified as a promising target for cancer therapy. However, known NAMPT inhibitors are characterized by weak clinical efficacy and dose-dependent toxicity. There is an urgent need to develop new NAMPT intervention strategies. Using the proteolysis-targeting chimera (PROTAC) technology, we designed and synthesized a series of new von Hippel-Lindau (VHL)-recruiting NAMPT-targeting PROTACs. A highly potent NAMPT degrader (B3) was successfully identified, which displayed excellent degradation activity (DC50 < 0.17 nM, Dmax > 90%) and antiproliferative potency against A2780 cells (IC50 = 1.5 nM). PROTAC B3 induced NAMPT depletion in a concentration- and time-dependent manner through the ubiquitin-proteasome system. Particularly, PROTAC B3 achieved good plasma exposure levels via intravenous injection, gained potent tumor growth inhibition (TGI = 88.1%, 2 μM/kg) in the xenograft model, and demonstrated good biosafety without undesired toxicities. This study provides a highly potent VHL-recruiting NAMPT degrader for the treatment of ovarian cancer.