Discovery of potent NAMPT-Targeting PROTACs using FK866 as the warhead

Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for cancer therapy due to its strong correlation with nicotinamide adenine dinucleotide (NAD⁺) metabolism and tumorigenesis. Proteolysis targeting chimeras (PROTACs) provided an attractive strategy for developing NAMPT-targeting NAD⁺-depleting cancer drugs. Herein, a series of von Hippel-Lindau (VHL)-recruiting NAMPT-targeting PROTACs were designed using NAMPT inhibitor FK866 as the warhead. Among them, compound C5 degraded NAMPT (DC₅₀ = 31.7 nM) in a VHL- and proteasome-dependent manner. Moreover, compound C5 effectively inhibited the proliferation of A2780 cells (IC₅₀ = 30.6 nM) and significantly reduced the general cytotoxicity of FK866 to normal cells.