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.

ACKNOWLEDGMENTS

We thank colleagues at Gemin X Pharmaceuticals for valuable scientific discussions. We thank Marcela White (Brain Tumor Bank) for tissue samples, Louis Gaboury (Universite de Montréal) for help with immunohistochemical analyses, and Nobumasa Hara for the generous gift of the NAPRT1 antibody.

Disclosure of financial conflicts of interest: Mark Watson, Anne Roulston, Laurent Bélec, Xavier Billot, Richard Marcellus, Cynthia Bernier, Stephane Branchaud, Helen Chan, Kenza Dairi, Karine Gilbert, Henady Isakau, Daniel Goulet, Michel-Olivier Gratton, Anne Jang, Abdelkrim Khadir, Elizabeth Koch, Manon Lavoie, Denis Paquette, and Pierre Beauparlant are or were employees of Gemin X Pharmaceuticals Inc. Gordon C. Shore is a cofounder and shareholder of Gemin X Pharmaceuticals Inc.