Teglarinad Chloride

GMX1777 exhibits unusually potent anti-tumor activity in preclinical animal models. The novel mechanism of action of GMX1778 supports the clinical use of GMX1777 as an anti-cancer agent. Moreover, the strong dependency of cancer cells on NAD+ to support DNA repair suggests a strong rationale for the use of GMX1777 in combination with DNA damaging agents for future trials.

The cytotoxicity of GMX1777, a prodrug of GMX1778, occurs exclusively through its ability to selectively inhibit nicotinamide phosphoribosyl transferase (NAMPRT). Tumor cells have elevated NAMPRT, an enzyme involved in the biosynthesis of oxidized nicotinamide adenine dinucleotide (NAD+). These cells have a high rate of NAD+ turnover due to elevated glycolysis and high ADP-ribosylation activity required for DNA repair, genome stability and telomere maintenance. These latter characteristics make cancer cells more susceptible to NAMPRT inhibition than normal cells. Although the mechanism of action of GMX1778 was initially believed to include NF-κB inhibition, a transcriptional factor that plays a role in cancer cell survival, NF-κB inhibition occurs as a consequence of ATP loss following NAMPRT inhibition and NAD+ decline.