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 Experiment | |
|---|---|
| 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. |
| Concentrations | ~100 nM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| 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 |
| Dosages | ~250 mg/kg |
| Administration | p.o. |
| Molecular Weight | 371.86 |
| Formula | C19H22ClN5O |
| CAS Number | 200484-11-3 |
| Solubility (25°C) | DMSO: ≥ 60 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
| Related NAMPT Products |
|---|
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NAMPT degrader-3 is a NAMPT degrader, depending on VHL- and proteasome manner. |
| Nampt activator-3
NAMPT activator-3, a NAT derivative, is a NAMPT activator with an EC50 of 2.6 μM and a KD of 132 nM. |
| Nampt-IN-8
Nampt-IN-8 (Compound 10d) is an NAMPT inhibitor with an IC50 of 0.183 μM. Nampt-IN-8 is also a relatively good NQO1 substrate. Nampt-IN-8 induces cell apoptosis and ROS. |
| GNE-618
GNE-618 is a potent, orally active nicotinamide phosphoribosyl transferase (NAMPT) inhibitor with an IC50 of 6 nM. GNE-618 depletes NAD levels and induces tumor cell death. Anti-tumor activity. |
| GPP78
GPP78 (CAY10618) is a potent Nampt inhibitor with an IC50 of 3.0 nM for nicotinamide adenine dinucleotide (NAD) depletion. GPP78 is cytotoxic to neuroblastoma cell line SH-SY5Y cells with an IC50 of 3.8 nM by inducing autophagy. GPP78 has anti-cancer and anti-inflammatory effects. |
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