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    NVP-CGM097
    NVP-CGM097

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V2654
    CAS #: 1313363-54-0Purity ≥98%

    Description: NVP-CGM097 (also known as CGM-097, CGM 097, CGM 097, NVP CGM097) is a  novel, highly potent, orally bioavailable and selective MDM2 ( (human homolog of double minute 2) inhibitor with IC50 of 1.7±0.1 nM for hMDM2 and with anticancer activity. 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. 

    Related CAS#:1313367-56-4 (NVP-CGM097 sulfate)

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    Molecular Weight (MW)659.26 
    FormulaC38H47ClN4O4 
    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) 
    Other infoChemical Name: (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one
    InChi Key: CLRSLRWKONPSRQ-IIPSPAQQSA-N
    InChi Code: InChI=1S/C38H47ClN4O4/c1-25(2)47-35-22-33-28(20-34(35)46-5)21-36(44)43(38(33)27-8-10-29(39)11-9-27)32-16-14-30(15-17-32)41(4)23-26-6-12-31(13-7-26)42-19-18-40(3)37(45)24-42/h8-11,14-17,20,22,25-26,31,38H,6-7,12-13,18-19,21,23-24H2,1-5H3/t26-,31-,38-/m0/s1
    SMILES Code: O=C1N(C2=CC=C(N(C)C[[email protected]]3CC[[email protected]](N4CC(N(C)CC4)=O)CC3)C=C2)[[email protected]@H](C5=CC=C(Cl)C=C5)C6=C(C=C(OC)C(OC(C)C)=C6)C1
    SynonymsCGM-097, CGM 097, CGM 097, NVP CGM097; CGM097; CGM-097; CGM 097; NVPCGM097; NVPCGM 097; NVPCGM-097; NVP CGM097; NVP CGM 097; NVP CGM-097.


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    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: NVP-CGM097 binds to human MDM2 with an IC50 of 1.7 nM and shows high selectivity over MDM4 (IC50=2000 nM). NVP-CGM097 is about four times more potent than Nutlin-3a (IC50=8 nM). In addition, NVP-CGM097 shows 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 significantly inhibits the proliferation of cells expressing wild-type p53, while sparing the p53 null cells with a 35-58-fold difference. NVP-CGM097 is 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. In addition, NVP-CGM097 activity against the p53:MDM2 interaction is assessed in proliferation assays using either wild-type p53 or p53 null cells. NVP-CGM097 significantly inhibits the proliferation of cells expressing wild-type p53, while sparing the p53 null cells with a 35-58-fold difference. NVP-CGM097 inhibtis HCT116 (p53WT/WT) with IC50 of 454±136 nM. 


    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. 

    In VivoAfter 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 modelSprague-Dawley rat 
    Formulation & DosageFormulated in NMP:PEG200 (30:70); 1 mg/kg; i.v. 
    ReferencesJ Med Chem. 2015 Aug 27;58(16):6348-58; Neuroendocrinology. 2016 Nov 21.  


    These protocols are for reference only. InvivoChem does not independently validate these methods.

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