NAMPT (nicotinamide phosphoribosyltransferase)

Class

Small molecule enzyme inhibitor (selective hyperbolic NAMPT inhibitor)

Pathway

NAD+ salvage biosynthesis pathway

NAMPT (nicotinamide phosphoribosyltransferase) is the rate-limiting enzyme in the NAD+ salvage pathway, the route by which cells regenerate nicotinamide adenine dinucleotide (NAD+) from the breakdown product nicotinamide. NAD+ is an essential cofactor for hundreds of redox reactions and is also consumed by enzymes involved in DNA repair and metabolic signaling, meaning cells must continuously replenish it. Many cancer cells have unusually high NAD+ turnover, driven by elevated proliferation, DNA repair activity, and metabolic demand, and rely heavily on the salvage pathway rather than slower alternative synthesis routes. Blocking NAMPT depletes intracellular NAD+, starving these cells of a cofactor needed for energy production and repair, which can trigger cell death preferentially in high-demand tumor cells. This mechanism has been explored across several cancer types, particularly those with metabolic vulnerabilities or loss of backup NAD+ synthesis routes. A notable pharmacological detail here is the description as a 'hyperbolic' inhibitor: rather than driving enzyme activity toward complete shutdown at high concentration, this class of molecule caps inhibition at a partial, self-limiting level. This distinguishes it from earlier full inhibitors and is intended to preserve enough NAD+ in normal tissues while still stressing more NAD+-dependent tumor cells.