The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors.
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.
Watson
Mark
M
Gemin X Pharmaceuticals Canada Inc., 3576 Avenue du Parc, Suite 4310, Montréal, Québec, Canada. mwatson@geminx.com
Roulston
Anne
A
Bélec
Laurent
L
Billot
Xavier
X
Marcellus
Richard
R
Bédard
Dominique
D
Bernier
Cynthia
C
Branchaud
Stéphane
S
Chan
Helen
H
Dairi
Kenza
K
Gilbert
Karine
K
Goulet
Daniel
D
Gratton
Michel-Olivier
MO
Isakau
Henady
H
Jang
Anne
A
Khadir
Abdelkrim
A
Koch
Elizabeth
E
Lavoie
Manon
M
Lawless
Michael
M
Nguyen
Mai
M
Paquette
Denis
D
Turcotte
Emilie
E
Berger
Alvin
A
Mitchell
Matthew
M
Shore
Gordon C
GC
Beauparlant
Pierre
P
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
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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