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Molecular and Cellular Biology, November 2009, p. 5872-5888, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00112-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Small Molecule GMX1778 Is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors{triangledown}

Mark Watson,1*,{dagger} Anne Roulston,1,{dagger} Laurent Bélec,1 Xavier Billot,1 Richard Marcellus,1 Dominique Bédard,1 Cynthia Bernier,1 Stéphane Branchaud,1 Helen Chan,1 Kenza Dairi,1 Karine Gilbert,1 Daniel Goulet,1 Michel-Olivier Gratton,1 Henady Isakau,1 Anne Jang,1 Abdelkrim Khadir,1 Elizabeth Koch,1 Manon Lavoie,1 Michael Lawless,1 Mai Nguyen,2 Denis Paquette,1 Émilie Turcotte,1 Alvin Berger,3,{ddagger} Matthew Mitchell,3 Gordon C. Shore,1,2 and Pierre Beauparlant1

Gemin X Pharmaceuticals Canada Inc., Montréal, Québec, Canada,1 Department of Biochemistry and Goodman Cancer Center, McGill University, Montréal, Québec, Canada,2 Metabolon Inc., Durham, North Carolina3

Received 23 January 2009/ Returned for modification 16 March 2009/ Accepted 7 August 2009

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.

* Corresponding author. Mailing address: Gemin X Pharmaceuticals Canada Inc., 3576 Avenue du Parc, Suite 4310, Montréal, Québec, Canada H2X 2H7. Phone: (514) 281-8989. Fax: (514) 281-1065. E-mail: mwatson{at}geminx.com. For material requests: gshore{at}geminx.com

{triangledown} Published ahead of print on 24 August 2009.

{dagger} M.W. and A.R. contributed equally to this work.

{ddagger} Present address: Cargill Inc., Wayzata, MN 55391-2313.

Molecular and Cellular Biology, November 2009, p. 5872-5888, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00112-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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