title: The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors.
abstract: GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe findings indicating that GMX1778 is a potent and specific inhibitor of the NAD(+) biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD(+) turnover, which makes NAD(+) modulation an attractive target for anticancer therapy. Selective inhibition by GMX1778 of NAMPT blocks the production of NAD(+) and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA), which permits NAD(+) repletion via NA phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that high frequencies of glioblastomas, neuroblastomas, and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be widended in the treatment animals bearing NAPRT1-deficient tumors by coadministration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers.
authors.affiliation: Gemin X Pharmaceuticals Canada Inc., 3576 Avenue du Parc, Suite 4310, Montréal, Québec, Canada. mwatson@geminx.com
authors.forename: Mark
authors.initials: M
authors.lastname: Watson
authors.forename: Anne
authors.initials: A
authors.lastname: Roulston
authors.forename: Laurent
authors.initials: L
authors.lastname: Bélec
authors.forename: Xavier
authors.initials: X
authors.lastname: Billot
authors.forename: Richard
authors.initials: R
authors.lastname: Marcellus
authors.forename: Dominique
authors.initials: D
authors.lastname: Bédard
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bernier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Branchaud
authors.forename: Helen
authors.initials: H
authors.lastname: Chan
authors.forename: Kenza
authors.initials: K
authors.lastname: Dairi
authors.forename: Karine
authors.initials: K
authors.lastname: Gilbert
authors.forename: Daniel
authors.initials: D
authors.lastname: Goulet
authors.forename: Michel-Olivier
authors.initials: MO
authors.lastname: Gratton
authors.forename: Henady
authors.initials: H
authors.lastname: Isakau
authors.forename: Anne
authors.initials: A
authors.lastname: Jang
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Khadir
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Koch
authors.forename: Manon
authors.initials: M
authors.lastname: Lavoie
authors.forename: Michael
authors.initials: M
authors.lastname: Lawless
authors.forename: Mai
authors.initials: M
authors.lastname: Nguyen
authors.forename: Denis
authors.initials: D
authors.lastname: Paquette
authors.forename: Emilie
authors.initials: E
authors.lastname: Turcotte
authors.forename: Alvin
authors.initials: A
authors.lastname: Berger
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitchell
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Shore
authors.forename: Pierre
authors.initials: P
authors.lastname: Beauparlant
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003486:Cyanides / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D009243:NAD / Q000096:biosynthesis*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D009525:Niacin / Q000008:administration & dosage / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012266:Ribose / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D009243:NAD; D009525:Niacin; D012266:Ribose; D054409:Nicotinamide Phosphoribosyltransferase
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