Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step in NAD⁺ biosynthesis via salvage of NAM formed from catabolism of NAD⁺ by proteins with NADase activity (e.g., PARPs, SIRTs, CD38). Depletion of NAD⁺ in aging, neurodegeneration, and metabolic disorders is addressed by NAD⁺ supplementation. Conversely, NAMPT inhibitors have been developed for cancer therapy: many discovered by phenotypic screening for cancer cell death have low nanomolar potency in cellular models. No NAMPT inhibitor is yet FDA-approved. The ability of inhibitors to act as NAMPT substrates may be associated with efficacy and toxicity. Some 3-pyridyl inhibitors become 4-pyridyl activators or “NAD⁺ boosters”. NAMPT positive allosteric modulators (N-PAMs) and boosters may increase enzyme activity by relieving substrate/product inhibition. Binding to a “rear channel” extending from the NAMPT active site is key for inhibitors, boosters, and N-PAMs. A deeper understanding may fulfill the potential of NAMPT ligands to regulate cellular life and death.