RG-7112

Name: RG-7112
Brand: Selleck Chemicals
SKU: S7030
Rating: 5 (7 reviews)

For research use only.

Catalog No.S7030 Synonyms: RO5045337

7 publications

CAS No. 939981-39-2

RG7112 (RO5045337) is an orally bioavailable and selective p53-MDM2 inhibitor with HTRF IC50 of 18 nM.

Selleck's RG-7112 has been cited by 7 publications

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Biological Activity

Description

RG7112 (RO5045337) is an orally bioavailable and selective p53-MDM2 inhibitor with HTRF IC50 of 18 nM.

Targets

Mdm2 ^[1]
(Cell-free assay)

11 nM(Kd)

In vitro

RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies. RG7112 binds MDM2 with high affinity (K_D of 10.7 nM), blocking its interactions with p53 in vitro. A crystal structure of the RG7112–MDM2 complex reveals that the small molecule binds in the p53 pocket of MDM2, mimicking the interactions of critical p53 amino acid residues. Treatment of cancer cells expressing wild-type p53 with RG7112 activates the p53 pathway, leading to cell-cycle arrest and apoptosis. RG7112 shows potent antitumor activity against a panel of solid tumor cell lines. However, its apoptotic activity varies widely with the best response observed in osteosarcoma cells with MDM2 gene amplification. ^[1]

Assay

Methods	Test Index	PMID
Western blot	MDM2 / PARP / Cleaved PARP; PubMed: 30022047 Cell Death Dis U138MG, LN18, and A1207 cells were treated with RG7112 for 12 h at the indicated concentrations. p21, MDM2, p53, and PARP levels were examined by immunoblotting. Actin was used as a loading control. p-TP53 / PUMA / Survivin ; PubMed: 27659536 Oncotarget Induction of TP53 phosphorylation and TP53 target proteins (TP21 and PUMA), as determined by western blotting. Cleaved PARP and survivin were also assessed to detect proapoptotic signaling	30022047 27659536
Immunofluorescence	p53 / p21; PubMed: 30022047 Cell Death Dis An image-based immunofluorescence assay for p21 (green), p53 (red) and DAPI (blue) in A1207 cells treated with DMSO, RG7112 (2 μM), AMG232 (2 μM), and Camptothecin (10 μM) for 72 h are shown.	30022047
Growth inhibition assay	Cell viability; PubMed: 30022047 Cell Death Dis Cell numbers of U373MG, LN18, U251MG, A1207, DBTRG-05MG, and U87MG cells treated with different concentrations (0.07–54 μM) of RG7112.	30022047

In vivo

RG7112 activates p53 pathway and induces apoptosis in tumor cells in vivo. Oral administration of RG7112 to human xenograft-bearing mice at nontoxic concentrations caused dose-dependent changes in proliferation/apoptosis biomarkers as well as tumor inhibition and regression. Notably, RG7112 is highly synergistic with androgen deprivation in LNCaP xenograft tumors. ^[1]

Protocol

Animal Research: ^[1]	- Collapse Animal Models: SJSA-1, SJSA-1luc2, and MHM xenografted Balb/c nude mice Dosages: 25–200 mg/kg Administration: oral (Only for Reference)

References

[1] Vu B, et al. ACS Med Chem Lett. 2013, 4(5):466-9.

Solubility (25°C)

In vitro	DMSO	100 mg/mL (137.68 mM)
	Water	Insoluble
	Ethanol	'100 mg/mL
In vivo	Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 1% CMC Na For best results, use promptly after mixing.	14mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information Download RG-7112 SDF

Molecular Weight	726.28
Formula	C₃₈H₄₈Cl₂N₄O₄S
CAS No.	939981-39-2
Storage	3 years-20°C powder 2 years-80°C in solvent
Synonyms	RO5045337
Smiles	CCOC1=C(C=CC(=C1)C(C)(C)C)C2=NC(C(N2C(=O)N3CCN(CC3)CCCS(=O)(=O)C)(C)C4=CC=C(C=C4)Cl)(C)C5=CC=C(C=C5)Cl

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

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Step 2: Enter the in vivo formulation (Different batches have different solubility ratios, please contact Selleck to provide you with the correct ratio)

% DMSO+ % + % Tween 80+ % ddH₂O

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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 DMSO master liquid, next addμL PEG300， mix and clarify, next addμL Tween 80，mix and clarify, next add μL ddH₂O，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.

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

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Mdm2 Signaling Pathway Map

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RG-7112