Home>>Signaling Pathways>> Cell Cycle/Checkpoint>> Aurora Kinase>>BI-847325

BI-847325

Catalog No.GC17828

dual inhibitor of MEK and Aurora kinases

Products are for research use only. Not for human use. We do not sell to patients.

BI-847325 Chemical Structure

Cas No.: 1207293-36-4

Size Price Stock Qty
5mg
$76.00
In stock
25mg
$233.00
In stock
100mg
$490.00
In stock

Tel:(909) 407-4943 Email: sales@glpbio.com

Customer Reviews

Based on customer reviews.

  • GlpBio Citations

    GlpBio Citations
  • Bioactive Compounds Premium Provider

    Bioactive Compounds Premium Provider

Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

View current batch:

Protocol

Kinase experiment:

Assays are run in the presence of 100 μM ATP using 10 μM of substrate. 30 μL PROTEIN-MIX in 25% DMSO and incubated for 15 min at room temperature. 10 μL PEPTIDE-MIX is added, the mixture is incubated for 60 min at RT and stopped by adding 180 μL 6.4% TCA (final concentration: 5%). Incorporated phosphate is measured in a scintillation counter and IC50 values are calculated using a sigmoidal curve analysis program with variable hill slope[1].

Cell experiment:

Cells are plated in 96-well format and BI 847325 is added 24 hours after cell seeding. At the same time, a “time zero” untreated cell plate is fixed. Compound is serially diluted and assayed over 8 concentrations in triplicates. After 72 h incubation, cells are fixed and stained with fluorescent nuclear dye. Concentration–response curves are analyzed using a four-parameter log-logistic function without upper or lower limitation. GI50 are calculated[1].

Animal experiment:

Mice: Tumor grafted female BomTac:NMRI-Foxn1nu mice are used in the study. BI 847325 is dissolved in 0.5% Natrosol 250 HX with 3% Tween 80 and sonicated until a homogenous suspension is obtained, then 1 M HCl is added and the suspension is vortexed and sonicated again. MEK inhibitors GSK 1120212 and AZD 6244 are suspended in 1% or 0.5% Natrosol, respectively. An administration volume of 10 mL/kg body weight is used and compounds are administered orally with a gavage needle at the indicated dose and schedule. Tumor volumes are measured and mice are inspected daily for clinical signs and body weight is determined daily[1].

References:

[1]. Sini P, et al. Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases. Mol Cancer Ther. 2016 Oct;15(10):2388-2398.

Background

BI 847325 is a dual inhibitor of Ras-mitogen-activated protein kinase kinases (MEK) and Aurora kinases [1,2]. BI 847325 inhibits MEK1 and MEK2 with IC50 values of 25 and 4 nM, respectively. For inhibiting the activity of Aurora A, B and C, IC50 values are 3, 25 and 15 nM, respectively [1].

The RAS-dependent MAP kinase signaling pathway is important in the regulation of cell survival and proliferation. It is hard to design direct inhibitors of RAS proteins. MEK is a downstream kinase of MAP kinase [1]. MEK is a ERK kinase [3].

In cells treated with BI 847325, based on levels of phospho-histone H3 (pHH3) and phospho-ERK (pERK), EC50 values were determined. To KRAS-and-PI3Kα-mutant NCI-H460 cells, the EC50 value was 44 nM. To BRAF-mutant A375 cells, the EC50 value was 37 nM. In a panel of 240 cell lines from diverse tissues with diverse genetic background, BI 847325 produced a potent inhibition of cell proliferation with a gm GI50 value of 28 nM. In a subset of cell lines, BI 847325 induced cell death. These in vitro potency correlated with mutations in BRAF or RAS, significantly [1].

In nude mouse xenograft models of cutaneous melanoma (A375, mutant BRAF) and NSCLC (Calu-6, mutant KRAS), BI 847325 at a daily oral dose of 10 mg/kg produced complete inhibition of tumor growth. In animals with A375 tumors, treatment with BI 847325 significantly reduced levels of both pHH3 and pERK in the tumors compared to controls [1].

References:
[1].  Sini P, Gürtler U, Zahn SK, et al. Pharmacological characterization of BI 847325, a dual inhibitor of MEK and Aurora kinases. Cancer Research, 2012, 72(8 Supplement): 1919-1919.
[2].  Hideshima T, Chauhan D, Richardson P, et al. NF-κB as a therapeutic target in multiple myeloma. Journal of Biological Chemistry, 2002, 277(19): 16639-16647.
[3].  Rommel C, Clarke BA, Zimmermann S, et al. Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science, 1999, 286(5445): 1738-1741..

Chemical Properties

Cas No. 1207293-36-4 SDF
Chemical Name (Z)-3-(3-(((4-((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-6-yl)-N-ethylpropiolamide
Canonical SMILES CCNC(C#CC1=CC=C2C(NC(/C2=C(NC3=CC=C(CN(C)C)C=C3)/C4=CC=CC=C4)=O)=C1)=O
Formula C29H28N4O2 M.Wt 464.56
Solubility DMF: 16 mg/ml,DMF:PBS(pH 7.2)(1:6): 0.14 mg/ml,DMSO: 5 mg/ml,Ethanol: 0.3 mg/ml Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

Prepare stock solution
1 mg 5 mg 10 mg
1 mM 2.1526 mL 10.7629 mL 21.5257 mL
5 mM 0.4305 mL 2.1526 mL 4.3051 mL
10 mM 0.2153 mL 1.0763 mL 2.1526 mL
  • Molarity Calculator

  • Dilution Calculator

Mass
=
Concentration
x
Volume
x
MW*
 
 
 
**When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and MSDS / CoA (available online).

Calculate

In vivo Formulation Calculator (Clear solution)

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

mg/kg g μL

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Calculation results:

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

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, 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.
3. All of the above co-solvents are available for purchase on the GlpBio website.

Reviews

Review for BI-847325

Average Rating: 5 ★★★★★ (Based on Reviews and 8 reference(s) in Google Scholar.)

5 Star
100%
4 Star
0%
3 Star
0%
2 Star
0%
1 Star
0%
Review for BI-847325

GLPBIO products are for RESEARCH USE ONLY. Please make sure your review or question is research based.

Required fields are marked with *

You may receive emails regarding this submission. Any emails will include the ability to opt-out of future communications.