CHS-828 (GMX1778) is a potent and specific inhibitor of NAMPT with IC50 and Kd value of <25 nM and 120 nM, respectively. CHS 828 kill tumour cells by inhibiting the nuclear factor-kappaB translocation but unlikely through down-regulation of proteasome. GMX1778 induces NAD+ depletion through inhibition of NAD+ biosynthesis, followed by ATP depletion and ultimately resulted in cell death. GMX1778 suppresses nuclear factor-kappa B activity in cancer cells through downregulation of IKK activity (IC50=8 nM).
In vivo: GMX1778 (250 mg/kg, p.o.) shows marked antitumoural activity against three different human neuroendocrine tumours, midgut carcinoid (GOT1), pancreatic carcinoid (BON), and medullary thyroid carcinoma (GOT2), transplanted in nude mice.
|Cell lines||HeLa cells|
|Preparation method||Serial dilutions of GMX1778 in DMSO are performed to achieve a final concentration of 0.2% DMSO. Relative ATP levels after 72 h are determined using a ViaLight HS high-sensitivity cytotoxicity and cell proliferation BioAssay kit per the manufacturer's instructions. For GMX1778 cytotoxicity rescue experiments, cells are treated with NA (10 μM) or NMN (100 μM) simultaneously with GMX1778. Sigmoidal dose-response curves are generated by nonlinear regression analysis of variable slope using GraphPad Prism version 4.00 (GraphPad Software) to calculate 50% inhibitory (IC50) values.|
|Incubation time||72 h|
|Animal models||Nude mice bearing midgut carcinoid (GOT1), pancreatic carcinoid (BON) and medullary thyroid cancer (GOT2) tumors|
|Formulation||Suspended in 2% carboxymethyl cellulose in 0.9% saline|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 60 mg/mL|
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.
Cerna D, et al. J Biol Chem. 2012 Jun 22;287(26):22408-17. PMID: 22570471.
The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors.
Watson M, et al. Mol Cell Biol. 2009 Nov;29(21):5872-88. PMID: 19703994.
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