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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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1 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
2 Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA
3 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA
4 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
5 Metabolomics Core Facility, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA
6 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
7 Daiichi Sankyo, Inc., Global Business Development, Basking Ridge, NJ, USA
8 Daiichi Sankyo Co., Ltd, Shinagawa Research & Development Center, Tokyo, Japan
9 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
10 Department of Chemistry, Binghamton University, Binghamton, NY, USA