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.

Details

Title
Boosting NAD+ with a small molecule that activates NAMPT
Author
Gardell, Stephen J 1 ; Hopf, Meghan 1 ; Khan, Asima 1 ; Dispagna, Mauro 2 ; E Hampton Sessions 3 ; Falter, Rebecca 3 ; Kapoor, Nidhi 4 ; Brooks, Jeanne 5 ; Culver, Jeffrey 5 ; Petucci, Chris 5 ; Chen-Ting, Ma 6 ; Cohen, Steven E 7   VIAFID ORCID Logo  ; Tanaka, Jun 8   VIAFID ORCID Logo  ; Burgos, Emmanuel S 9   VIAFID ORCID Logo  ; Hirschi, Jennifer S 10 ; Smith, Steven R 1 ; Sergienko, Eduard 6 ; Pinkerton, Anthony B 6 

 Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA; Translational Research Institute for Metabolism and Diabetes, AdventHealth-Orlando, Orlando, FL, USA 
 Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA 
 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA 
 Translational Research Institute for Metabolism and Diabetes, AdventHealth-Orlando, Orlando, FL, USA; Metabolomics Core Facility, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA 
 Metabolomics Core Facility, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA 
 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA 
 Daiichi Sankyo, Inc., Global Business Development, Basking Ridge, NJ, USA 
 Daiichi Sankyo Co., Ltd, Shinagawa Research & Development Center, Tokyo, Japan 
 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA 
10  Department of Chemistry, Binghamton University, Binghamton, NY, USA 
Pages
1-12
Publication year
2019
Publication date
Jul 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2260416750
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.