Boosting NAD+ with a small molecule that activates NAMPT

  • Nat Commun. 2019 Jul 19;10(1):3241. doi: 10.1038/s41467-019-11078-z.
Stephen J Gardell  1  2 ,  Meghan Hopf  3  4 ,  Asima Khan  3  4 ,  Mauro Dispagna  3 ,  E Hampton Sessions  5 ,  Rebecca Falter  5 ,  Nidhi Kapoor  4  6 ,  Jeanne Brooks  6 ,  Jeffrey Culver  6 ,  Chris Petucci  6 ,  Chen-Ting Ma  7 ,  Steven E Cohen  8 ,  Jun Tanaka  9 ,  Emmanuel S Burgos  10 ,  Jennifer S Hirschi  11 ,  Steven R Smith  3  4 ,  Eduard Sergienko  7 ,  Anthony B Pinkerton  12
Affiliations
  • 1. Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, 32827, USA. [email protected].
  • 2. Translational Research Institute for Metabolism and Diabetes, AdventHealth-Orlando, Orlando, FL, 32804, USA. [email protected].
  • 3. Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, 32827, USA.
  • 4. Translational Research Institute for Metabolism and Diabetes, AdventHealth-Orlando, Orlando, FL, 32804, USA.
  • 5. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, 32827, USA.
  • 6. Metabolomics Core Facility, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, 32827, USA.
  • 7. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • 8. Daiichi Sankyo, Inc., Global Business Development, Basking Ridge, NJ, 07920, USA.
  • 9. Daiichi Sankyo Co., Ltd, Shinagawa Research & Development Center, Tokyo, 140-8710, Japan.
  • 10. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
  • 11. Department of Chemistry, Binghamton University, Binghamton, NY, 13902, USA.
  • 12. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. [email protected].
PMID: 31324777 DOI: 10.1038/s41467-019-11078-z
Abstract

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.

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