Boosting NAD+ with a small molecule that activates NAMPT

• Published in: Nature communications Vol. 10; no. 1; pp. 3241 - 12
• Main Authors: Gardell, Stephen J., Hopf, Meghan, Khan, Asima, Dispagna, Mauro, Hampton Sessions, E., Falter, Rebecca, Kapoor, Nidhi, Brooks, Jeanne, Culver, Jeffrey, Petucci, Chris, Ma, Chen-Ting, Cohen, Steven E., Tanaka, Jun, Burgos, Emmanuel S., Hirschi, Jennifer S., Smith, Steven R., Sergienko, Eduard, Pinkerton, Anthony B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.07.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 49; 49/47; 59; 631/154/555; 631/45; 64; 64/60; 692/308/153; 82/58; A549 Cells; Animals; Biocatalysis - drug effects; Cell division; Enzyme Activators - administration & dosage; Enzyme Activators - chemistry; Enzyme Activators - pharmacology; Enzymes; Feedback inhibition; Genomics; Humanities and Social Sciences; Humans; Inhibitors; Intracellular; Intracellular Space - drug effects; Intracellular Space - metabolism; Ligands; Liver - drug effects; Liver - metabolism; Mammalian cells; Mice; Molecular Structure; multidisciplinary; NAD; NAD - metabolism; Nicotinamide; Nicotinamide Mononucleotide - metabolism; Nicotinamide phosphoribosyltransferase; Nicotinamide Phosphoribosyltransferase - metabolism; Pharmacology; Phosphoribosyltransferase; Phosphorylation - drug effects; R&D; Research & development; Science; Science (multidisciplinary); Small Molecule Libraries - administration & dosage; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11078-z

Pharmacological strategies that boost intracellular NAD + are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase production of nicotinamide mononucleotide (NMN), the predominant NAD + precursor in mammalian cells. A high-throughput screen for NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound that is structurally similar to active-site directed NAMPT inhibitors and blocks binding of these inhibitors to NAMPT. SBI-797812 shifts the NAMPT reaction equilibrium towards NMN formation, increases NAMPT affinity for ATP, stabilizes phosphorylated NAMPT at His247, promotes consumption of the pyrophosphate by-product, and blunts feedback inhibition by NAD + . These effects of SBI-797812 turn NAMPT into a “super catalyst” that more efficiently generates NMN. Treatment of cultured cells with SBI-797812 increases intracellular NMN and NAD + . Dosing of mice with SBI-797812 elevates liver NAD + . Small molecule NAMPT activators such as SBI-797812 are a pioneering approach to raise intracellular NAD + and realize its associated salutary effects. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate determining step for NAD + synthesis and is of interest as a drug target. Here the authors identify and characterize a small molecule NAMPT activator SBI-797812, elucidate its mode of action and show that it increases intracellular NMN and NAD + levels in cultured cells and elevates liver NAD + in mice.