NVP-CGM097 (Synonyms: CGM097) |
Catalog No.GC12647
One-Click Copy Product Info
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NVP-CGM097 est un inhibiteur puissant et sélectif de MDM2 avec une IC50 de 1,7 ± 0,1 nM pour hMDM2.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1313363-54-0
Sample solution is provided at 25 µL, 10mM.
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NVP-CGM097 is a potent and selective MDM2 inhibitor with IC50 of 1.7±0.1 nM for hMDM2.
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[1].
NVP-CGM097 is 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, as judged by elevation of p21 mRNA levels, a pharmacodynamic (PD) indicator for p53 activity. p21 mRNA levels are found to increase concomitantly with levels of NVP-CGM097 in tumor-bearing rats dosed at 30 mg/kg. The PD response is biphasic and prolonged up to 24 h. Additional p53 target genes such as MDM2 and PUMA mRNA levels are assessed in the tumor samples as well and showed a similar behavior. Daily treatment with NVP-CGM097 dose dependently and significantly inhibits SJSA-1 tumor growth in rats. It promotes stable disease at 20 mg/kg, which is associated with a plasma AUC0-24 of 163 μM•h. After iv administration, the total blood clearance (CL) of NVP-CGM097 is 5 mL/min per kg for mouse, 7 mL/min per kg for rat, 3 mL/min per kg for dog, and 4 mL/min per kg for monkey. The apparent terminal half-life (t1/2) is long in rodents and monkey (6-12 h) but is comparatively longer in dogs (20 h). After oral dosing, NVP-CGM097 is well absorbed with Tmax occurring between 1 and 4.5 h in all species tested[1].
References:
[1]. Holzer P, et al. Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors. J Med Chem. 2015 Aug 27;58(16):6348-58
| Cell experiment [1,2]: | |
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Cell lines |
Neuroblastoma cell lines, HCT116 cells |
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Preparation method |
Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
24 h |
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Applications |
The combination of NVP-CGM097 with NVP-LDK378 promoted apoptosis in ALK mutant and p53 WT neuroblastoma cell lines. NVP-LDK378 inhibited ALK phosphorylation and NVP-CGM097 caused induction of p53 and its downstream target genes in these cell lines. NVP-CGM097 significantly inhibited the proliferation of cells expressing wild-type p53, while sparing the p53 null cells with a 35-58-fold difference. NVP-CGM097 significantly redistributed wild-type p53 into the cell nucleus with an IC50 of 0.224 μM. NVP-CGM097 inhibited HCT116 (p53WT/WT) with IC50 of 454 ± 136 nM. |
| Animal experiment [1,3]: | |
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Animal models |
NOD.SCID.IL2R-/- (NSG) mice engraftmented with hCD45+/hCD19+ cells, ALK mutant neuroblastoma models, MDM2-amplified SJSA-1 human tumor model |
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Dosage form |
Intravenous injection, 30 mg/kg, Daily |
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Application |
In NOD.SCID.IL2R-/- (NSG) mice engraftmented with hCD45+/hCD19+ cells, CGM097 ultimately became moribund from progressive leukemia. CGM097 significantly upregulated the expression of 11 genes at the 26 hour timepoint, including the canonical p53 targets BBC3, CDKN1A and MDM2. CGM097 markedly improved overall survival. NVP-LDK378 and NVP-CGM097 combination resulted in complete tumor regression and markedly prolonged survival in neuroblastoma xenograft models. NVP-CGM097 inhibited the interaction between p53 and MDM2 and reactivated the p53 pathway in a MDM2-amplified SJSA-1 human tumor model. NVP-CGM097 (30 mg/kg) increased p21 mRNA levels in tumor-bearing rats. Daily treatment with NVP-CGM097 dose-dependently inhibited SJSA-1 tumor growth in rats. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Wang H Q, Battalagine L, Liang J, et al. The Mdm2 inhibitor NVP-CGM097 enhances the anti-tumor activity of NVP-LDK378 in ALK mutant neuroblastoma models[J]. 2014. [2]. Holzer P, et al. Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors. J Med Chem. 2015 Aug 27;58(16):6348-58. [3]. Townsend E C, DeSouza T, Murakami M A, et al. The MDM2 Inhibitor NVP-CGM097 Is highly active in a randomized preclinical trial of B-cell acute lymphoblastic leukemia patient derived xenografts[J]. 2015. | |
| Cas No. | 1313363-54-0 | SDF | |
| Synonymes | CGM097 | ||
| Chemical 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 | ||
| Canonical SMILES | CC(OC(C=C1[C@]2([H])C3=CC=C(Cl)C=C3)=C(OC)C=C1CC(N2C4=CC=C(N(C[C@@]5([H])CC[C@@](N(CC6=O)CCN6C)([H])CC5)C)C=C4)=O)C | ||
| Formula | C38H47ClN4O4 | M.Wt | 659.26 |
| Solubility | DMF: 30 mg/ml,DMSO: 25 mg/ml,Ethanol: 30 mg/ml,Ethanol:PBS (pH 7.2) (1:3): 0.25 mg/ml | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.5169 mL | 7.5843 mL | 15.1685 mL |
| 5 mM | 303.4 μL | 1.5169 mL | 3.0337 mL |
| 10 mM | 151.7 μL | 758.4 μL | 1.5169 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL saline, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.50% Appearance: A solid
- COA (Certificate of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 32 reference(s) in Google Scholar.)