Wilsbacher et. al. supplement from Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

Wilsbacher, Julie L.; Cheng, Min; Cheng, Dong; Trammell, Samuel A.J.; Shi, Yan; Guo, Jun; Koeniger, Stormy L.; Kovar, Peter J.; He, Yupeng; Selvaraju, Sujatha; Heyman, H. Robin; Sorensen, Bryan K.; Clark, Richard F.; Hansen, T. Matthew; Longenecker, Kenton L.; Raich, Diana; Korepanova, Alla V.; Cepa, Steven; Towne, Danli L.; Abraham, Vivek C.; Tang, Hua; Richardson, Paul L.; McLoughlin, Shaun M.; Badagnani, Ilaria; Curtin, Michael L.; Michaelides, Michael R.; Maag, David; Buchanan, F. Gregory; Chiang, Gary G.; Gao, Wenqing; Rosenberg, Saul H.; Brenner, Charles; Tse, Chris

doi:10.1158/1535-7163.22503430.v1

15357163mct160819-sup-175333_2_unknown_upload_3975787_jjmjpx.pdf (1 MB)

Wilsbacher et. al. supplement from Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

journal contribution

posted on 2023-04-03, 14:43 authored by Julie L. Wilsbacher, Min Cheng, Dong Cheng, Samuel A.J. Trammell, Yan Shi, Jun Guo, Stormy L. Koeniger, Peter J. Kovar, Yupeng He, Sujatha Selvaraju, H. Robin Heyman, Bryan K. Sorensen, Richard F. Clark, T. Matthew Hansen, Kenton L. Longenecker, Diana Raich, Alla V. Korepanova, Steven Cepa, Danli L. Towne, Vivek C. Abraham, Hua Tang, Paul L. Richardson, Shaun M. McLoughlin, Ilaria Badagnani, Michael L. Curtin, Michael R. Michaelides, David Maag, F. Gregory Buchanan, Gary G. Chiang, Wenqing Gao, Saul H. Rosenberg, Charles Brenner, Chris Tse

Supplementary methods, tables S1-S3, and supplementary figures 1-7

Funding

AbbVie, Inc.

History

ARTICLE ABSTRACT

Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236–45. ©2017 AACR.