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AMG232

p53-MDM2 inhibitor, novel CAS# 1352066-68-2

AMG232

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Chemical structure

AMG232

3D structure

Chemical Properties of AMG232

Cas No. 1352066-68-2 SDF Download SDF
PubChem ID 58573469 Appearance Powder
Formula C28H35Cl2NO5S M.Wt 568.55
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 50 mg/mL (87.94 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-3-methyl-1-propan-2-ylsulfonylbutan-2-yl]-2-oxopiperidin-3-yl]acetic acid
SMILES CC(C)C(CS(=O)(=O)C(C)C)N1C(C(CC(C1=O)(C)CC(=O)O)C2=CC(=CC=C2)Cl)C3=CC=C(C=C3)Cl
Standard InChIKey DRLCSJFKKILATL-YWCVFVGNSA-N
Standard InChI InChI=1S/C28H35Cl2NO5S/c1-17(2)24(16-37(35,36)18(3)4)31-26(19-9-11-21(29)12-10-19)23(20-7-6-8-22(30)13-20)14-28(5,27(31)34)15-25(32)33/h6-13,17-18,23-24,26H,14-16H2,1-5H3,(H,32,33)/t23-,24-,26-,28-/m1/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.

Biological Activity of AMG232

DescriptionAMG232 is a potent, selective and orally bioavailable inhibitor of MDM2−p53 interaction with IC50 value of 9.1 nM in EdU cells .
TargetsMDM2−p53 interaction    
IC509.1 nM (in EdU cells)     

Protocol

Cell Assay [1]
Cell lines are plated in 96- or 384-well plates at optimum initial seeding densities to ensure that cells do not reach confluency by the end of the assay. The cells are treated with DMSO control or AMG 232 at various concentrations for 72 hours. CellTiter-Glo Luminescent Cell Viability or ATPlite 1step Luminescent assay kits are used to determine the numbers of viable cells. Luminescence is measured with an EnVision Multilabel Reader for each cell line at time zero (V0) before the addition of compounds, as well as after 72 hours of compound treatment. Growth inhibition (GI) is calculated on a 200-point scale according to the following equations, where V72 is luminescence of DMSO control at 72 hours and TV72 is luminescence of the compound-treated sample: if T72 > V0, then GI=100 × (1 − ((T72 − V0)/(V72 − V0))); if T72 < V0, then GI=100 × (1 − ((T72 − V0)/V0)). GI values of 0, 100, and 200 represent uninhibited cell growth (i.e., DMSO control), cell stasis, and complete cell killing, respectively. Dose-response curves are generated using XLFit software to calculate IC50 values for AMG 232 in each cell line tested.

Animal Administration [1]
SJSA-1 cells (5×106 cells with Matrigel at a ratio of 2:1), NCI-H460 cells (5 × 106 cells with Matrigel at a ratio of 2:1), A375sq2 (5 × 106 cells with Matrigel at a ratio of 2:1), or HCT116 (2 × 106 cells) are injected subcutaneously in the flank of female athymic nude mice (n=10/group). Treatment begin when tumors are established and approximately 200 mm3. AMG 232 is administered once per day by oral gavage. Cisplatin, carboplatin, doxorubicin, and CPT-11 are dosed once per week by i.p or i.v. (doxorubicin) injection. Combination treatment studies are performed in a blinded manner. Tumor dimensions are assessed twice weekly with a Pro-Max electronic digital caliper and tumor volume is calculated using the formula: length×width×height and expressed as mm3. Data are expressed as mean±SEM. Body weight is recorded twice weekly to assess tolerability. Analysis of p21 mRNA at the end of the xenograft studies is performed as described for the p21 pharmacodynamic assay.

References:
[1]. Canon J, et al. The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents. Mol Cancer Ther. 2015 Mar;14(3):649-58. [2]. Ye Q, et al. Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation. Xenobiotica. 2015;45(8):681-92. [3]. Rew Y, et al. Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014 Aug 14;57(15):6332-41.

AMG232 Dilution Calculator

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Preparing Stock Solutions of AMG232

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7589 mL 8.7943 mL 17.5886 mL 35.1772 mL 43.9715 mL
5 mM 0.3518 mL 1.7589 mL 3.5177 mL 7.0354 mL 8.7943 mL
10 mM 0.1759 mL 0.8794 mL 1.7589 mL 3.5177 mL 4.3972 mL
50 mM 0.0352 mL 0.1759 mL 0.3518 mL 0.7035 mL 0.8794 mL
100 mM 0.0176 mL 0.0879 mL 0.1759 mL 0.3518 mL 0.4397 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 AMG232

AMG-232 is a novel inhibitor of p53-MDM2 with IC50 value of 9.2 nM [1].

Tumor protein p53 (p53) is a very unstable protein with a half-life ranging from 5 to 30 min and participates in a variety of anticancer processes, such as inducing cell apoptosis and inhibiting angiogenesis. Mouse double minute 2 homolog (MDM2), also named as E3 ubiquitin-protein ligase Mdm2, involves in mediating p53 tumor suppressor. It has been conclusively demonstrated p53 is under-expressed in tumor cells [2].

AMG-232 is a potent p53-MDM2 interaction inhibitor and is regarded as a promising drug in clinic. When tested with SJSA-1 tumor cell line, AMG-232 treatment resulted in cell-cycle arrest and inhibition of tumor cell proliferation via binding to MDM2 protein and robustly inducing p53 activity. It was shown that p53-MDM2 bond rang from a Kd of 60 to 700 nM Depending on the length of p53 peptide [3].

In mouse model with SJSA-1 tumor cells subcutaneous xenograft, co-administration of AMG-232 and chemotherapies induced DNA damage and p53 activity which resulted in significantly superior antitumor efficacy and regression through arresting cell growth and inducting apoptosis [3].

References:
[1].  Rew, Y., et al., Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction. J Med Chem, 2014. 57(24): p. 10499-511.
[2].  Moll, U.M. and O. Petrenko, The MDM2-p53 interaction. Mol Cancer Res, 2003. 1(14): p. 1001-8.
[3].  Canon, J., et al., The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents. Mol Cancer Ther, 2015. 14(3): p. 649-58.

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References on AMG232

Potent effect of the MDM2 inhibitor AMG232 on suppression of glioblastoma stem cells.[Pubmed:30022047]

Cell Death Dis. 2018 Jul 18;9(8):792.

Testing new ways to identify untapped opportunities for glioblastoma therapies remains highly significant. Amplification and overexpression of MDM2 gene is frequent in glioblastoma and disrupting the MDM2-p53 interaction is a promising strategy to treat the cancer. RG7112 is the first-in class inhibitor and recently discovered AMG232 is the most potent MDM2 inhibitor known to date. Here, we compared the effects of these two clinical MDM2 inhibitors in six glioblastoma cell lines and ten patient-derived glioblastoma stem cells. Targeted sequencing of the TP53, MDM2 genes and whole transcriptome analysis were conducted to verify genetic status associated with sensitivity and resistance to the drugs. Although TP53 wild-type glioblastoma cell lines are similarly sensitive to AMG232 and RG7112, we found that four TP53 wild-type out of ten patient-derived glioblastoma cells are much more sensitive to AMG232 than RG7112 (average IC50 of 76 nM vs. 720 nM). Among these, 464T stem cells containing MDM2 gene amplification were most sensitive to AMG232 with IC50 of 5.3 nM. Moreover, AMG232 exhibited higher selectivity against p53 wild-type cells over p53 mutant stem cells compared to RG7112 (average selectivity of 512-fold vs. 16.5-fold). Importantly, we also found that AMG232 is highly efficacious in three-dimensional (3D) tumor spheroids growth and effectively inhibits the stemness-related factors, Nestin and ZEB1. Our data provide new evidence that glioblastoma stem cells have high susceptibility to AMG232 suggesting the potential clinical implications of MDM2 inhibition for glioblastoma treatment. These will facilitate additional preclinical and clinical studies evaluating MDM2 inhibitors in glioblastoma and direct further efforts towards developing better MDM2-targeted therapeutics.

A yeast two-hybrid system for the screening and characterization of small-molecule inhibitors of protein-protein interactions identifies a novel putative Mdm2-binding site in p53.[Pubmed:29121928]

BMC Biol. 2017 Nov 9;15(1):108.

BACKGROUND: Protein-protein interactions (PPIs) are fundamental to the growth and survival of cells and serve as excellent targets to develop inhibitors of biological processes such as host-pathogen interactions and cancer cell proliferation. However, isolation of PPI inhibitors is extremely challenging. While several in vitro assays to screen for PPI inhibitors are available, they are often expensive, cumbersome, and require large amounts of purified protein. In contrast, limited in vivo assays are available to screen for small-molecule inhibitors of PPI. METHODS: We have engineered a yeast strain that is suitable for screening of small-molecule inhibitors of protein-protein interaction using the Yeast 2-hybrid Assay. We have optimised and validated the assay using inhibitors of the p53-Mdm2 interaction and identified a hitherto unreported putative Mdm2-binding domain in p53. RESULTS: We report a significantly improved and thoroughly validated yeast two-hybrid (Y2H) assay that can be used in a high throughput manner to screen for small-molecule PPI inhibitors. Using the p53-Mdm2 interaction to optimize the assay, we show that the p53-Mdm2 inhibitor nutlin-3 is a substrate for the yeast ATP-binding cassette (ABC) transporter Pdr5. By deleting nine ABC transporter-related genes, we generated a ABC9Delta yeast strain that is highly permeable to small molecules. In the ABC9Delta strain, p53-Mdm2 interaction inhibitors, like AMG232 and MI-773, completely inhibited the p53-Mdm2 interaction at nanomolar concentrations in the Y2H assay. In addition, we identified a conserved segment in the core DNA-binding domain of p53 that facilitates stable interaction with Mdm2 in yeast cells and in vitro. CONCLUSION: The Y2H assay can be utilized for high-throughput screening of small-molecule inhibitors of PPIs and to identify domains that stabilize PPIs.

Description

AMG 232 is a potent, selective and orally available inhibitor of p53-MDM2 interaction, with an IC50 of 0.6 nM. AMG 232 binds to MDM2 with a Kd of 0.045 nM.

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