Nicotinamide phosphoribosyltransferase (NAMPT) is an enzyme that catalyzes the synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (NM) and PRPP. Therefore, NAMPT plays an important role in the cyclic biosynthetic pathway of nicotinamide adenine dinucleotide (NAD). Especially, NAMPT acts as an extracellular proinflammatory cytokine, able to induce cellular expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and to promote pre-B cell colony formation. GPP78 is a potent NAMPT inhibitor.

Nampt inhibition induces a potent cytotoxic activity against multiple myeloma cell lines in vitro and in vivo. Moreover, Nampt inhibition also triggers a marked increase in autophagy. NAMPT inhibitors are beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Furthermore, NAMPT inhibitors can ameliorate animal model symptomatology of inflammatory diseases such as arthritis, endotoxic shock, and autoimmune encephalitis. Of these, FK866 is a specific inhibitor of NAMPT. FK866 is capable of reducing the secondary injury and partly reduce permanent damage administered after spinal cord injury (SCI). GPP78 is an analogue of FK866. Meanwhile, GPP78 displays the same effects in the histological score and similar improvements in the motor activity of SCI animals.

To investigate the activity of GPP78, researchers incubate neuroblastoma cell line SH-SY5Y cells with GPP78 for 48 hours. In particular, researchers evaluate cell viability by the MTT method.
Crucially, GPP78 displays an IC50 for cytotoxicity in vitro of 3.8±0.3 nM and an IC50 for NAD depletion of 3.0±0.4 nM. As a result, the inhibition of NAD synthesis or salvage pathways act as a novel target for antitumoral drugs.

To summarise, GPP78 is a novel potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitor inducing autophagy with anti-cancer and anti-inflammatory effects.

Esposito E, et al. The NAMPT inhibitor FK866 reverts the damage in spinal cord injury. J Neuroinflammation. 2012 Apr 10;9:66.