Discovery and characterization of novel nonsubstrate and substrate NAMPT inhibitors

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

doi:10.1158/1535-7163.mct-16-0819

Discovery and characterization of novel nonsubstrate and substrate NAMPT inhibitors

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. AbrahamHua 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

^*Corresponding author for this work

9 Citations (Scopus)

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.

Original language	English
Journal	Molecular Cancer Therapeutics
Volume	16
Issue number	7
Pages (from-to)	1236-1245
Number of pages	10
ISSN	1535-7163
DOIs	https://doi.org/10.1158/1535-7163.mct-16-0819
Publication status	Published - 2017
Externally published	Yes

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Wilsbacher, J. L., Cheng, M., Cheng, D., Trammell, S. A. J., Shi, Y., Guo, J., Koeniger, S. L., Kovar, P. J., He, Y., Selvaraju, S., Heyman, H. R., Sorensen, B. K., Clark, R. F., Hansen, T. M., Longenecker, K. L., Raich, D., Korepanova, A. V., Cepa, S., Towne, D. L., ... Tse, C. (2017). Discovery and characterization of novel nonsubstrate and substrate NAMPT inhibitors. Molecular Cancer Therapeutics, 16(7), 1236-1245. https://doi.org/10.1158/1535-7163.mct-16-0819

Wilsbacher, JL, Cheng, M, Cheng, D, Trammell, SAJ, Shi, Y, Guo, J, Koeniger, SL, Kovar, PJ, He, Y, Selvaraju, S, Heyman, HR, Sorensen, BK, Clark, RF, Hansen, TM, Longenecker, KL, Raich, D, Korepanova, AV, Cepa, S, Towne, DL, Abraham, VC, Tang, H, Richardson, PL, McLoughlin, SM, Badagnani, I, Curtin, ML, Michaelides, MR, Maag, D, Buchanan, FG, Chiang, GG, Gao, W, Rosenberg, SH, Brenner, C & Tse, C 2017, 'Discovery and characterization of novel nonsubstrate and substrate NAMPT inhibitors', Molecular Cancer Therapeutics, vol. 16, no. 7, pp. 1236-1245. https://doi.org/10.1158/1535-7163.mct-16-0819

@article{2c1b13380d1747028f4254aefc37dfae,

title = "Discovery and characterization of novel nonsubstrate and substrate NAMPT inhibitors",

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.",

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

year = "2017",

doi = "10.1158/1535-7163.mct-16-0819",

language = "English",

volume = "16",

pages = "1236--1245",

journal = "Molecular Cancer Therapeutics",

issn = "1535-7163",

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T1 - Discovery and characterization of novel nonsubstrate and substrate NAMPT inhibitors

AU - Wilsbacher, Julie L.

AU - Cheng, Min

AU - Cheng, Dong

AU - Trammell, Samuel A.J.

AU - Shi, Yan

AU - Guo, Jun

AU - Koeniger, Stormy L.

AU - Kovar, Peter J.

AU - He, Yupeng

AU - Selvaraju, Sujatha

AU - Heyman, H. Robin

AU - Sorensen, Bryan K.

AU - Clark, Richard F.

AU - Hansen, T. Matthew

AU - Longenecker, Kenton L.

AU - Raich, Diana

AU - Korepanova, Alla V.

AU - Cepa, Steven

AU - Towne, Danli L.

AU - Abraham, Vivek C.

AU - Tang, Hua

AU - Richardson, Paul L.

AU - McLoughlin, Shaun M.

AU - Badagnani, Ilaria

AU - Curtin, Michael L.

AU - Michaelides, Michael R.

AU - Maag, David

AU - Buchanan, F. Gregory

AU - Chiang, Gary G.

AU - Gao, Wenqing

AU - Rosenberg, Saul H.

AU - Brenner, Charles

AU - Tse, Chris

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1158/1535-7163.mct-16-0819

DO - 10.1158/1535-7163.mct-16-0819

M3 - Journal article

C2 - 28468779

AN - SCOPUS:85024380688

SN - 1535-7163

VL - 16

SP - 1236

EP - 1245

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 7

ER -

Discovery and characterization of novel nonsubstrate and substrate NAMPT inhibitors

Abstract

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