Hydrophobic tagging-induced degradation of NAMPT in leukemia cells

Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy to its crucial role in cancer metabolism. Despite the therapeutic potential of NAMPT enzymatic inhibitors, their effectiveness is limited by dose-related toxicity and the inability to suppress nonenzymatic functions of extracellular NAMPT (eNAMPT). Herein, we designed and synthesized the first hydrophobic tagging NAMPT degraders. Among them, compound NH-11 selectively degraded NAMPT in leukemia cells through the ubiquitin-proteasome system. Compound NH-11 effectively induced apoptosis and showed low toxicity to normal cells, representing a promising anti-leukemia lead compound.