2. Academic Validation
  3. Boosting NAD+ with a small molecule that activates NAMPT

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

Affiliations

  • 1 Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, 32827, USA. stephen.gardell@adventhealth.com.
  • 2 Translational Research Institute for Metabolism and Diabetes, AdventHealth-Orlando, Orlando, FL, 32804, USA. stephen.gardell@adventhealth.com.
  • 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. apinkerton@sbpdiscovery.org.
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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