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NVP-CGM097

CAS# 1313363-54-0

NVP-CGM097

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Chemical structure

NVP-CGM097

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Chemical Properties of NVP-CGM097

Cas No. 1313363-54-0 SDF Download SDF
PubChem ID 53240420 Appearance Powder
Formula C38H47ClN4O4 M.Wt 659.26
Type of Compound N/A Storage Desiccate at -20°C
Synonyms CGM097
Solubility DMSO : ≥ 50 mg/mL (75.84 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name (1S)-1-(4-chlorophenyl)-6-methoxy-2-[4-[methyl-[[4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl]methyl]amino]phenyl]-7-propan-2-yloxy-1,4-dihydroisoquinolin-3-one
SMILES CC(C)OC1=C(C=C2CC(=O)N(C(C2=C1)C3=CC=C(C=C3)Cl)C4=CC=C(C=C4)N(C)CC5CCC(CC5)N6CCN(C(=O)C6)C)OC
Standard InChIKey CLRSLRWKONPSRQ-CPOWQTMSSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Protocol

Cell Assay [1]
Two pairs of cell lines are used to assess NVP-CGM097 p53-dependent antiproliferative effects: (1) an isogenic pair of HCT116 cell lines either expressing wild-type p53 or knocked-out for the p53 gene and (2) a nonisogenic pair of osteosarcoma cell lines either endogenously expressing wild-type p53 and amplified for MDM2 (SJSA-1 cells) or null for p53 (SAOS-2 cells)[1].

Animal Administration [1]
Rats[1] Female athymic rats bearing subcutaneous xenotransplants of SJSA-1 tumors (n=5-12) are treated at 5, 10, 20, or 30 mg/kg or three times a week on Monday, Wednesday, and Friday (3qw M, W, F) at 30 or 70 mg/kg po for 14 days. Plasma AUCs are determined at the end of the study. Positive numbers indicate the percentage of tumor growth inhibition (T/C); negative numbers indicate the percentage of tumor regression.

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

NVP-CGM097 Dilution Calculator

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Preparing Stock Solutions of NVP-CGM097

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.5169 mL 7.5843 mL 15.1685 mL 30.337 mL 37.9213 mL
5 mM 0.3034 mL 1.5169 mL 3.0337 mL 6.0674 mL 7.5843 mL
10 mM 0.1517 mL 0.7584 mL 1.5169 mL 3.0337 mL 3.7921 mL
50 mM 0.0303 mL 0.1517 mL 0.3034 mL 0.6067 mL 0.7584 mL
100 mM 0.0152 mL 0.0758 mL 0.1517 mL 0.3034 mL 0.3792 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on NVP-CGM097

NVP-CGM097 is a potent and selective MDM2 inhibitor with IC50 of 1.7±0.1 nM for hMDM2.

In Vitro: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].

In Vivo: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

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References on NVP-CGM097

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53wild type Neuroendocrine Tumor Cell Line GOT1.[Pubmed:27871087]

Neuroendocrinology. 2018;106(1):1-19.

BACKGROUND/AIMS: The tumor suppressor p53 is depleted in many tumor cells by the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2) through MDM2/p53 interaction. A novel target for inhibiting p53 degradation and for causing reexpression of p53wild type is inhibition of MDM2. The small molecule NVP-CGM097 is a novel MDM2 inhibitor. We investigated MDM2 inhibition as a target in neuroendocrine tumor cells in vitro. METHODS: Human neuroendocrine tumor cell lines from the pancreas (BON1), lung (NCI-H727), and midgut (GOT1) were incubated with the MDM2 inhibitor NVP-CGM097 (Novartis) at concentrations from 4 to 2,500 nM. RESULTS: While p53wild type GOT1 cells were sensitive to NVP-CGM097, p53mutated BON1 and p53mutated NCI-H727 cells were resistant to NVP-CGM097. Incubation of GOT1 cells with NVP-CGM097 at 100, 500, and 2,500 nM for 96 h caused a significant decline in cell viability to 84.9 +/- 9.2% (p < 0.05), 77.4 +/- 6.6% (p < 0.01), and 47.7 +/- 9.2% (p < 0.01). In a Western blot analysis of GOT1 cells, NVP-CGM097 caused a dose-dependent increase in the expression of p53 and p21 tumor suppressor proteins and a decrease in phospho-Rb and E2F1. Experiments of co-incubation of NVP-CGM097 with 5-fluorouracil, temozolomide, or everolimus each showed additive antiproliferative effects in GOT1 cells. NVP-CGM097 and 5-fluorouracil increased p53 and p21 expression in an additive manner. CONCLUSIONS: MDM2 inhibition seems a promising novel therapeutic target in neuroendocrine tumors harboring p53wild type. Further investigations should examine the potential role of MDM2 inhibitors in neuroendocrine tumor treatment.

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.[Pubmed:26181851]

J Med Chem. 2015 Aug 27;58(16):6348-58.

As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.

A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097.[Pubmed:25965177]

Elife. 2015 May 12;4.

Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53-HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53-HDM2 inhibitors, such as NVP-CGM097.

Description

NVP-CGM097 is a potent and selective MDM2 inhibitor with IC50 of 1.7±0.1 nM for hMDM2.

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