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.

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT) Activity by Small Molecule GMX1778 Regulates Reactive Oxygen Species (ROS)-mediated Cytotoxicity in a p53- and Nicotinic Acid Phosphoribosyltransferase1 (NAPRT1)-dependent Manner

“…Based on the observation that NAPRT1 expression was defective in certain cancer cells, the synthetic lethality strategy has been proposed to specifically target tumors that are lacking in NAPRT1 expression. Although this strategy appears attractive and feasible based on the previous report (20,21), the efficacy of GMX1778 might be compromised because of the possibility that GMX1778 might also induce ROS in normal tissues. Because ROS may be one of the major sources of normal tissue toxicities for approximately half of Food and Drug Administration-approved chemotherapeutics (17), it would be critical to improve a therapeutic index of GMX1778 by minimizing normal tissue damage incurred by ROS.…”

“…ROS Are Not Induced by GMX1778 in Normal Cells-In NAPRT1 wild-type cells, cytotoxicity of GMX1778 can be prevented by vitamin B 3 (niacin) restoration of NAD ϩ via NAPRT1 (20,21). To determine whether niacin could also rescue NAPRT1 wild-type cells by modulating ROS levels, we first tested expression levels of NAPRT1 in various cancer and normal cell lines.…”

“…Although both pathways are employed to generate NAD ϩ , in cells expressing endogenous NAPRT1, only the NA added in the salvage pathway can increase cellular levels of NAD ϩ and reduce cytotoxicity by an oxidizing agent (18,19). GMX1778 (CHS 828; teglarinad) is a potent inhibitor of NAMPT that exerts a cytotoxic effect by decreasing the cellular level of NAD ϩ (20,21). GMX1778 has been shown to synergize with ionizing radiation in head and neck cancer tumor models (22).…”

“…When applied in a metronomic treatment regimen of lower doses at frequent intervals, GMX1777, an intravenously administered pro-drug of GMX1778, regressed neuroblastomas in a preclinical model (23). Furthermore, exogenous addition of NA rescues NAD ϩ depletion via the NAPRT1-dependent salvage pathway (20,21). Thus, in tumors deficient in nicotinamide phosphoribosyltransferase, targeting NAMPT with GMX1778 may provide a novel synthetic lethal therapeutic approach by inducing metabolic stress.…”

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

“…Administration of FK866 in vivo suppresses growth of murine renal cell carcinoma and mammary carcinoma in mice (Drevs et al, 2003;Muruganandham et al, 2005). Similarly, another NAMPT inhibitor, GMX1778, exhibits significant anti-tumor activity (Watson et al, 2009). However, precise roles of NAMPT in cancer are poorly understood.…”