product name NVP-CGM097
Description: NVP-CGM097 (CGM-097, CGM 097, CGM 097, NVP CGM097) is a novel, highly potent and selective MDM2 inhibitor. It binds to the p53 binding-site of the Mdm2 protein, disrupting the interaction between both proteins, leading to an activation of the p53 pathway. Upon oral administration, p53/HDM2 interaction inhibitor CGM097 inhibits the binding of the HDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this HDM2-p53 interaction, the proteosome-mediated enzymatic degradation of p53 is inhibited, which may result in the restoration of p53 signaling and, thus, the p53-mediated induction of tumor cell apoptosis.
References: J Med Chem. 2015 Aug 27;58(16):6348-58; Neuroendocrinology. 2016 Nov 21.
659.26
Formula
C38H47ClN4O4
CAS No.
1313363-54-0
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 65 mg/mL (98.6 mM)
Water: <1 mg/mL
Ethanol: 65 mg/mL (98.6 mM)
Solubility (In vivo)
Synonyms
CGM-097, CGM 097, CGM 097, NVP CGM097
other peoduct :
| In Vitro |
In vitro activity: NVP-CGM097 binding to MDM2 is species dependent. It was shown to be selective for the p53:MDM2 interaction compared to the p53:MDM4 interaction (1176-fold selectivity) and the Ras:Raf interaction (3000-fold selectivity). In addition, NVP-CGM097 showed no significant activity against Bcl-2:Bak, Bcl-2:Bad, Mcl-1:Bak, Mcl-1:NOXA, XIAP:BIR3, and c-IAP:BIR3 protein-protein interactions. NVP-CGM097 was able to significantly redistribute wild-type p53 into the cell nucleus with an IC50 of 0.224 μM, demonstrating its ability to inhibit the p53:MDM2 interaction in living cells. NVP-CGM097 treatment leads to p53 nuclear translocation that results in cell growth inhibition in a p53-dependent manner. Kinase Assay: Cell Assay: Cells (Bon1 cells, NCI-H727 cells, Got1 cells) were seeded in appropriate densities (Bon1 cells: 1500 cells/well, NCI-H727 cells: 2000 cells/well, Got1 cells: 50000 cells/well) into 96-well plates and grown for 24 hrs in complete medium containing serum/antibiotic. The next day, the cells were incubated with various concentrations of NVP-CGM097 (0.1 nM-2500 nM), 5-fluorouracil (100 nM-100 µM), streptozotocin (1 nM-100 µM), temozolomide (1 µM-1 mM), everolimus (10 nM) or octreotide (100 nM-10 µM) in 10 % FBS medium (antibiotic-free). After 48 hrs, 96 hrs, 144 hrs or 216 hrs the metabolic activity was measured with “Cell Titer 96 Aqueous One Solution” cell proliferation assay. The measurement was performed at 492 nm with an ELISA plate reader. |
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| In Vivo | After iv administration, the total blood clearance (CL) of NVP-CGM097 was 5 mL/min/kg for mouse, 7 mL/min/kg for rat, 3 mL/min/kg for dog, and 4 mL/min/kg for monkey. On the basis of the respective hepatic blood flows, NVP-CGM097 showed a consistent low total blood CL in all species (5-10% of hepatic blood flow). The apparent terminal half-life (t1/2) was long in rodents and monkey (6-12 h) but was comparatively longer in dogs (20 h). After oral dosing, the compound was well absorbed with Tmax occurring between 1 and 4.5 h in all species tested. The oral bioavailability (%F) was high in mouse, rat, and dog and moderate in monkey. NVP-CGM097 was able to inhibit the interaction between p53 and MDM2 and reactivate the p53 pathway in vivo in a MDM2-amplified SJSA-1 human tumor model. p21 mRNA levels were found to increase concomitantly with levels of compound 1 in tumor-bearing rats dosed at 30 mg/kg. Daily treatment with NVP-CGM097 dose dependently and significantly inhibited SJSA-1 tumor growth in rats. |
| Animal model | Sprague-Dawley rat |
| Formulation & Dosage | Formulated in NMP:PEG200 (30:70); 1 mg/kg; i.v. |
| References | J Med Chem. 2015 Aug 27;58(16):6348-58; Neuroendocrinology. 2016 Nov 21. |
