Journal article
Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors
Molecular cancer therapeutics, Vol.16(7), pp.1236-1245
07/2017
DOI: 10.1158/1535-7163.MCT-16-0819
PMID: 28468779
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 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 cellular activity or antitumor efficacy. .
Details
- Title: Subtitle
- Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors
- Creators
- Julie L Wilsbacher - AbbVie Inc., North Chicago, Illinois. julie.wilsbacher@abbvie.comMin Cheng - AbbVie Inc., North Chicago, IllinoisDong Cheng - AbbVie Inc., North Chicago, IllinoisSamuel A J Trammell - Department of Biochemistry Carver College of Medicine, University of Iowa, Iowa City, IowaYan Shi - AbbVie Inc., North Chicago, IllinoisJun Guo - AbbVie Inc., North Chicago, IllinoisStormy L Koeniger - AbbVie Inc., North Chicago, IllinoisPeter J Kovar - AbbVie Inc., North Chicago, IllinoisYupeng He - AbbVie Inc., North Chicago, IllinoisSujatha Selvaraju - AbbVie Inc., North Chicago, IllinoisH Robin Heyman - AbbVie Inc., North Chicago, IllinoisBryan K Sorensen - AbbVie Inc., North Chicago, IllinoisRichard F Clark - AbbVie Inc., North Chicago, IllinoisT Matthew Hansen - AbbVie Inc., North Chicago, IllinoisKenton L Longenecker - AbbVie Inc., North Chicago, IllinoisDiana Raich - AbbVie Inc., North Chicago, IllinoisAlla V Korepanova - AbbVie Inc., North Chicago, IllinoisSteven Cepa - AbbVie Inc., North Chicago, IllinoisDanli L Towne - AbbVie Inc., North Chicago, IllinoisVivek C Abraham - AbbVie Inc., North Chicago, IllinoisHua Tang - AbbVie Inc., North Chicago, IllinoisPaul L Richardson - AbbVie Inc., North Chicago, IllinoisShaun M McLoughlin - AbbVie Inc., North Chicago, IllinoisIlaria Badagnani - AbbVie Inc., North Chicago, IllinoisMichael L Curtin - AbbVie Inc., North Chicago, IllinoisMichael R Michaelides - AbbVie Inc., North Chicago, IllinoisDavid Maag - AbbVie Inc., North Chicago, IllinoisF Gregory Buchanan - AbbVie Inc., North Chicago, IllinoisGary G Chiang - AbbVie Inc., North Chicago, IllinoisWenqing Gao - AbbVie Inc., North Chicago, IllinoisSaul H Rosenberg - AbbVie Inc., North Chicago, IllinoisCharles Brenner - Department of Biochemistry Carver College of Medicine, University of Iowa, Iowa City, IowaChris Tse - AbbVie Inc., North Chicago, Illinois
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.16(7), pp.1236-1245
- DOI
- 10.1158/1535-7163.MCT-16-0819
- PMID
- 28468779
- NLM abbreviation
- Mol Cancer Ther
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Publisher
- United States
- Grant note
- CIHR
- Language
- English
- Date published
- 07/2017
- Academic Unit
- Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9983788430202771
Metrics
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