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VRT752271

ERK1/ERK2 inhibitor CAS# 869886-67-9

VRT752271

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VRT752271

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Chemical Properties of VRT752271

Cas No. 869886-67-9 SDF Download SDF
PubChem ID 11719003 Appearance Powder
Formula C21H22Cl2N4O2 M.Wt 433.33
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Ulixertinib
Solubility DMSO : ≥ 45 mg/mL (103.85 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-4-[5-chloro-2-(propan-2-ylamino)pyridin-4-yl]-1H-pyrrole-2-carboxamide
SMILES CC(C)NC1=NC=C(C(=C1)C2=CNC(=C2)C(=O)NC(CO)C3=CC(=CC=C3)Cl)Cl
Standard InChIKey KSERXGMCDHOLSS-LJQANCHMSA-N
Standard InChI InChI=1S/C21H22Cl2N4O2/c1-12(2)26-20-8-16(17(23)10-25-20)14-7-18(24-9-14)21(29)27-19(11-28)13-4-3-5-15(22)6-13/h3-10,12,19,24,28H,11H2,1-2H3,(H,25,26)(H,27,29)/t19-/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 VRT752271

DescriptionVRT752271 is a reversible, ATP-competitive inhibitor of ERK1 and ERK2 kinases, with IC50 of <0.3 nM against ERK2.In Vitro:VRT752271 (BVD-523) is a reversible, ATP-competitive inhibitor of ERK1 and ERK2 kinases, with IC50 of <0.3 nM against ERK2[1].In Vivo:In the pharmacokinetic study, the sensitivity and specificity of the assay are found to be sufficient for accurately characterizing the plasma pharmacokinetics of VRT752271 in Balb/C mice[1].

References:
[1]. Kumar R, et al. Determination of ulixertinib in mice plasma by LC-MS/MS and its application to a pharmacokinetic study in mice. J Pharm Biomed Anal. 2016 Jun 5;125:140-4. [2]. Ward RA, et al. Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2. J Med Chem. 2015 Jun 11;58(11):4790-801.

Protocol

Kinase Assay [2]
The MEK autophosphorylation assay is performed using the ADP Glo Kinase Assay kit. Activated MEK protein is expressed and purified in-house. Enzyme and substrate solutions are prepared in assay buffer consisting of 50 mM Tris (pH 7.5), 10 mM MgCl2, 0.1 mM EGTA, 10 mM DTT and 0.01 % Tween 20. 6 nM MEK protein is prepared in assay buffer and 2 µL is dispensed into each well of a 384-well white small volume medium bind plate containing test and reference control compounds. Compound plates are dosed with a 12 point dose response curve from 10 µM down to 0.0625 nM in order to calculate compound IC50s, with a total DMSO concentration in the assay of 1%. Following a 15 minute pre-incubation of enzyme and compound at room temperature, 2 µL of a 20 µM Ultra Pure ATP solution in assay buffer is added to the wells, and the reaction is allowed to progress for 90 minutes at room temperature before the addition of 4 µL ADP Glo reagent R1 to quench the reaction. The plate is incubated at room temperature for 45 minutes before the addition of 8 µL Kinase Detection Reagent, and then the luminescence signal is allowed to equilibrate for 60 minutes before the plates are read on a Pherastar plate reader.

Cell Assay [2]
A375 cells are cultured in cell media composed of DMEM, 10% (v/v) Foetal Calf Serum and 1% (v/v) L-Glutamine. After harvesting, cells are dispensed into black, 384-well Costar plates to give 200 cells per well in a total volume of 40 µL cell media, and are incubated overnight at 37°C, 90% relative humidity and 5% CO2 in a rotating incubator. Test compounds and reference controls are dosed directly into the cell plates, into the inner 308 wells, sing a Labcyte Echo 555 acoustic dispenser. The cells are dosed over a 12 point range from 30 µM down to 0.03 nM in order to calculate compound IC50s, with a total DMSO concentration in the assay of 0.3%. The cell plates are then incubated for 72 hours at 37°C. Cells are fixed and stained by the addition of 20 µL 12% formaldehyde in PBS/A (4% final concentration) and 1:2000 dilution of Hoechst 33342, with a 30 minute room temperature incubation, and then washed with PBS/A. A cell count is performed on the stained cell plates using a Cellomics ArrayScanTM VTI imaging platform. A Day 0 cell plate is also fixed, stained and read to generate a cell count baseline for determining compound cytotoxic effects as well as anti-proliferative effects.

References:
[1]. Kumar R, et al. Determination of ulixertinib in mice plasma by LC-MS/MS and its application to a pharmacokinetic study in mice. J Pharm Biomed Anal. 2016 Jun 5;125:140-4. [2]. Ward RA, et al. Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2. J Med Chem. 2015 Jun 11;58(11):4790-801.

VRT752271 Dilution Calculator

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Preparing Stock Solutions of VRT752271

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3077 mL 11.5386 mL 23.0771 mL 46.1542 mL 57.6928 mL
5 mM 0.4615 mL 2.3077 mL 4.6154 mL 9.2308 mL 11.5386 mL
10 mM 0.2308 mL 1.1539 mL 2.3077 mL 4.6154 mL 5.7693 mL
50 mM 0.0462 mL 0.2308 mL 0.4615 mL 0.9231 mL 1.1539 mL
100 mM 0.0231 mL 0.1154 mL 0.2308 mL 0.4615 mL 0.5769 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 VRT752271

VRT752271 is a pyrrole inhibitors of ERK protein kinase.

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References on VRT752271

Determination of ulixertinib in mice plasma by LC-MS/MS and its application to a pharmacokinetic study in mice.[Pubmed:27017572]

J Pharm Biomed Anal. 2016 Jun 5;125:140-4.

A sensitive, specific and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of ulixertinib in mice plasma using phenacetin as an internal standard (I.S.) as per regulatory guidelines. Sample preparation was accomplished through a protein precipitation procedure with acetonitrile:methanol mixture. Chromatographic separation was performed on Atlantis dC18 column using a binary gradient using mobile phase A (0.2% formic acid in water) and B (acetonitrile) at a flow rate of 0.60mL/min. Elution of ulixertinib and I.S. occurred at approximately 1.07 and 1.20min, respectively. The total chromatographic run time was 2.5min. A linear response function was established in the concentration range of 1.58-2054ng/mL. The intra- and inter-day accuracy and precisions were in the range of 2.11-11.8 and 5.80-11.4%, respectively. This novel method has been applied to a pharmacokinetic study in mice.

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib).[Pubmed:28939558]

Mol Cancer Ther. 2017 Nov;16(11):2351-2363.

Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAF(V600E)-mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to single-agent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway (NCT01781429, NCT02296242, and NCT02608229). Mol Cancer Ther; 16(11); 2351-63. (c)2017 AACR.

Description

Ulixertinib (BVD-523; VRT752271) is a potent, orally active, highly selective, ATP-competitive and reversible covalent inhibitor of ERK1/2 kinases, with an IC50 of <0.3 nM against ERK2. Ulixertinib (BVD-523; VRT752271) inhibits the phosphorylated ERK2 (pERK) and downstream kinase RSK (pRSK) in an A375 melanoma cell line.

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