GMX1778

GMX1778(CHS-828) is a potent inhibitor of NAD+ biosynthesis enzyme NAMPT with IC50 <25 nM.IC50 value: < 25 nM [1]Target: NAMPT inhibitorin vitro: The phosphoribosyltransferase activity of recombinant NAMPT was sensitive to inhibition by GMX1778 (IC50 < 25 nM) whereas the adenyltransferase activity of recombinant NMNAT1 was not. The Kd of recombinant NAMPT for GMX1778 labeled with a fluorescent tag (GMX1778-Alexa Fluor) was 120 nM. Overexpression of wild-type NAMPT was able to maintain a certain level of NAD+ under conditions of challenge with 3 nM GMX1778, but this effect was lost when cells were exposed to 300 nM GMX1778 [1]. GMX1778 increases intracellular ROS in cancer cells by elevating the superoxide level while decreasing the intracellular NAD(+) level. Notably, GMX1778 treatment does not induce ROS in normal cells. GMX1778-induced ROS can be diminished by adding nicotinic acid (NA) in a NA phosphoribosyltransferase 1 (NAPRT1)-dependent manner [2].in vivo: A 4-h iv infusion of NA (120 mg/kg of body weight) did not adversely affect the antitumor activity of a 24-h iv infusion of GMX1777 at a dose of 150 mg/kg or 650 mg/kg in the NAPRT1-deficient xenograft experiments. GMX1777 at 650 mg/kg is above the maximum tolerated dose. The administration of NA as a 4-h iv infusion immediately following treatment with 750 mg/kg GMX1777 reduced the mortality associated with toxic doses of GMX1777 [1].

Signaling Pathways >> Metabolic Enzyme/Protease >> Nampt

Research Areas >> Cancer

[1]. Watson M, et al. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors. Mol Cell Biol. 2009 Nov;29(21):5872-88.

[2]. Cerna D, et al. 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. J Biol Chem. 2012 Jun 22;287(26):22408-17.

FK866 (APO866, Daporinad) | P7C3 | STF 118804 | KPT-9274 | GNE-617 | Nampt-IN-1 | CB 300919 | CB30865