SCH772984

ERK1 and ERK2 inhibitor CAS# 942183-80-4

SCH772984

Catalog No. BCC1935----Order now to get a substantial discount!

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Quality Control of SCH772984

Number of papers citing our products

Chemical structure

SCH772984

3D structure

Chemical Properties of SCH772984

Cas No. 942183-80-4 SDF Download SDF
PubChem ID 24866313 Appearance Powder
Formula C33H33N9O2 M.Wt 587.67
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 14.29 mg/mL (24.32 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name (3R)-1-[2-oxo-2-[4-(4-pyrimidin-2-ylphenyl)piperazin-1-yl]ethyl]-N-(3-pyridin-4-yl-1H-indazol-5-yl)pyrrolidine-3-carboxamide
SMILES C1CN(CC1C(=O)NC2=CC3=C(C=C2)NN=C3C4=CC=NC=C4)CC(=O)N5CCN(CC5)C6=CC=C(C=C6)C7=NC=CC=N7
Standard InChIKey HDAJDNHIBCDLQF-RUZDIDTESA-N
Standard InChI InChI=1S/C33H33N9O2/c43-30(42-18-16-41(17-19-42)27-5-2-24(3-6-27)32-35-11-1-12-36-32)22-40-15-10-25(21-40)33(44)37-26-4-7-29-28(20-26)31(39-38-29)23-8-13-34-14-9-23/h1-9,11-14,20,25H,10,15-19,21-22H2,(H,37,44)(H,38,39)/t25-/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 SCH772984

DescriptionSCH772984 is a novel, specific inhibitor of ERK1/2 with IC50 values of 4 nM and 1 nM, respectively.
TargetsERK1ERK2    
IC504 nM1 nM    

Protocol

Cell experiment [1]:

Cell lines

melanoma cell lines (M408, M202, WM1366)

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

24 h; 500 nM

Applications

Treatment with SCH772984 for the sensitive M408 resulted in decreased pRSK, disappearance of pERK1/2, and slight induction of pMEK, with no change in total RSK, MEK, ERK 1/2, or AKT. For the resistant M202, a modest induction of pMEK with some decrease in pERK and pRSK was observed at 24 hours. Treatment with SCH772984 resulted in upregulation of pAKT levels for M408 and WM1366.

Animal experiment [2]:

Animal models

Nude mice

Dosage form

25 mg/kg; b.i.d; intraperitoneal injection

Application

The therapeutic effects of combining the CDK inhibitor Dinaciclib with inhibitors of ERK inhibitor SCH772984 were evaluated using two orthotopic patient-derived human pancreatic cancer xenograft models (Panc253 and Panc265). These models closely resemble the physiological and pathological conditions of pancreatic cancer in humans. A 2-3 mm3 tumor explant was implanted into the pancreas of nude mice and ultrasound imaging was used to measure the tumor size (3D) before randomization and treatment, which began when tumors grew to 50-100 mm3. The combination of Dinaciclib (20 mg/kg, i.p., t.i.w.) and SCH772984 (25 mg/kg, i.p., b.i.d.) dramatically inhibited the growth of primary orthotopic Panc265 (82.5%, p < 0.001) and Panc253 (95.7%, p <0.001) versus control, and also the number of metastatic lesions of both Panc265 (94.9%, p <0.001) and Panc253 (92.4%, p <0.02).

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.

References:

[1] Wong D J L, Robert L, Atefi M S, et al. Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma[J]. Molecular cancer, 2014, 13(1): 194.

[2] Hu C, Dadon T, Chenna V, et al. Abstract B263: Combined inhibition of cyclin-dependent kinases (Dinaciclib) and AKT (MK-2206) or ERK (SCH772984) dramatically blocks pancreatic tumor growth and metastases in patient-derived orthotopic xenograft models[J]. Molecular Cancer Therapeutics, 2013, 12(11 Supplement): B263-B263.

SCH772984 Dilution Calculator

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SCH772984 Molarity Calculator

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Preparing Stock Solutions of SCH772984

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7016 mL 8.5082 mL 17.0164 mL 34.0327 mL 42.5409 mL
5 mM 0.3403 mL 1.7016 mL 3.4033 mL 6.8065 mL 8.5082 mL
10 mM 0.1702 mL 0.8508 mL 1.7016 mL 3.4033 mL 4.2541 mL
50 mM 0.034 mL 0.1702 mL 0.3403 mL 0.6807 mL 0.8508 mL
100 mM 0.017 mL 0.0851 mL 0.1702 mL 0.3403 mL 0.4254 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 SCH772984

SCH772984, identified by an affinity-based mass spectroscopy high-throughput platform, is a novel, potent and ATP-competitive inhibition of ERK1 and ERK2 with 50% inhibition concentration IC50 values of 4 nmol/L and 1 nmol/L respectively. Although it displays behaviors of both type I and type II kinase inhibitors, SCH772984 is highly selective against only seven kinases, including CLK2, FLT4, GSG2, MAP4K4, MAPK1, MINK1, PRKD1 and TTK, out of a wide range of 300 tested with more than 50% inhibition at a concentration of 1 μmol/L. Study results have shown that SCH772984 potently inhibits tumor cells with mutations in BRAF, NRAS and KRAS at nanomolar concentrations.

Reference

Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S, Long B, Liu J, Dinunzio E, Windsor W, Zhang R, Zhao S, Angagaw MH, Pinheiro EM, Desai J, Xiao L, Shipps G, Hruza A, Wang J, Kelly J, Paliwal S, Gao X, Babu BS, Zhu L, Daublain P, Zhang L, Lutterbach BA, Pelletier MR, Philippar U, Siliphaivanh P, Witter D, Kirschmeier P, Bishop WR, Hicklin D, Gilliland DG, Jayaraman L, Zawel L, Fawell S, Samatar AA. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 2013 Jul;3(7):742-750

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References on SCH772984

Analgesic effect and possible mechanism of SCH772984 intrathecal injection on rats with bone cancer pain.[Pubmed:27275127]

Saudi Pharm J. 2016 May;24(3):354-62.

This study is to establish a model of rat tibial osteocarcinoma pain, intrathecally inject specific ERK1/2 inhibitors SCH772984, observe the analgesic effect, and discuss the influence of ERK-P90RSK-Fos signal path in bone cancer pain. Forty female SD rats were randomly divided into 5 groups. Establish a bone cancer pain model after putting the intrathecal tube 5d and determine the rats' mechanical withdrawal threshold (MWT) after tube 5d; 40 SD rats with intrathecal tube back 5d were randomly divided into 5 groups. Sham Group receives no medication, the other four respectively receive 5% DMSO 10 mul, SCH 0.1, 1.0, 10 mug (SCH dissolved in 10 mul 5% DMSO) intrathecally. Determine the rats' mechanical withdrawal threshold (MWT) before and after giving medication 1, 3, 6, 9, 12, 15, 18, 24 h, and 2 min spontaneous paw withdrawal. Western blot and immuno-fluorescence determine the expression condition of spinal cord dorsal horn of p-ERK, p-p90RSK and Fos protein. Intrathecal injection of SCH772984 has analgesic effects on rats with bone cancer pain, and the effects enhance with increasing dose; intrathecal injection of SCH772984 10 mug could greatly reduce the expression of spinal dorsal horn Fos protein. Injecting walker 256 tumor cells into rats' tibia could cause behavior changes, such as idiopathic pain sensitivity and pain; the intrathecal tube almost has no effect on motor function of rats; ERK1/2 is involved in bone cancer pain, and intrathecal injection of ERK1/2 specific inhibitors SCH772984 10 mug may effectively relieve bone cancer pain.

Antitumor activity of the ERK inhibitor SCH772984 [corrected] against BRAF mutant, NRAS mutant and wild-type melanoma.[Pubmed:25142146]

Mol Cancer. 2014 Aug 20;13:194.

BACKGROUND: In melanoma, dysregulation of the MAPK pathway, usually via BRAF(V600) or NRAS(Q61) somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAF(V600), NRAS mutant, or wild-type melanoma. METHODS: The 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined. RESULTS: Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 muM; intermediately sensitive, IC50 1-2 muM; and resistant, >2 muM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAF(V600) mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis. CONCLUSIONS: Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors.

Description

SCH772984 is a highly selective and ATP-competitive ERK inhibitor, with IC50s of 4 and 1 nM for ERK1 and ERK2, respectively. SCH772984 has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations.

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