Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

Molecular Cancer Therapeutics
Julie L WilsbacherChris Tse

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.

References

Dec 13, 2006·Trends in Biochemical Sciences·Peter BelenkyCharles Brenner
Sep 2, 2009·Microbiology and Molecular Biology Reviews : MMBR·Francesca GazzanigaCharles Brenner
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Alexei A Vagin, Alexei Teplyakov
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul EmsleyKevin D Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Clemens VonrheinGérard Bricogne
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Garib N MurshudovAlexei A Vagin
Apr 27, 2011·Current Medicinal Chemistry·E S Burgos
Apr 17, 2012·Acta Crystallographica. Section D, Biological Crystallography·Oliver S SmartGérard Bricogne
Sep 29, 2012·Nature Reviews. Cancer·Alberto ChiarugiM Ziegler
Apr 27, 2013·Journal of Medicinal Chemistry·Xiaozhang ZhengKenneth W Bair
May 18, 2013·Journal of Medicinal Chemistry·Ubaldina GalliArmando A Genazzani
Jul 19, 2013·Journal of Medicinal Chemistry·Xiaozhang ZhengKenneth W Bair
Oct 8, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·David S ShamesLisa D Belmont
Nov 10, 2013·Neoplasia : an International Journal for Oncology Research·Yang XiaoThomas O'Brien
Nov 26, 2013·Chemistry & Biology·Szu-Chieh Mei, Charles Brenner
Jan 1, 2013·Computational and Structural Biotechnology Journal·Samuel Aj Trammell, Charles Brenner
Oct 31, 2014·The Journal of Biological Chemistry·Christopher Del NagroThomas O'Brien
Feb 25, 2015·Pharmacology & Therapeutics·Deepak SampathPeter S Dragovich
Aug 6, 2015·Cell Metabolism·Samuel A J Trammell, Charles Brenner
May 28, 2016·Scientific Reports·Samuel A J TrammellCharles Brenner
Oct 11, 2016·Nature Communications·Samuel A J TrammellCharles Brenner
Oct 12, 2016·Nature Communications·Joanna RatajczakCarles Cantó

Citations

Jul 16, 2019·MedChemComm·Paul L RichardsonAnil Vasudevan
Jan 30, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Steven CassarBruce LeRoy
Jun 2, 2020·Frontiers in Pharmacology·Ubaldina GalliAmbra A Grolla

Related Concepts

Related Feeds

Cancer Metabolism: Therapeutic Targets

Targeting the mechanisms by which cancer cells acquire energy for metabolic needs is a therapeutic target. Discover the latest research on cancer metabolism and therapeutic targets.

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.