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S63845

Catalog No.GC12621

MCL1 inhibitor

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

S63845 Chemical Structure

Cas No.: 1799633-27-4

Size Price Stock Qty
10mM (in 1mL DMSO)
$319.00
In stock
1mg
$69.00
In stock
5mg
$231.00
In stock
10mg
$350.00
In stock
25mg
$770.00
In stock

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

View current batch:

Protocol

Cell experiment [1]:

Cell lines

Haematological cancer-derived cell lines, Myeloma cell lines, Human lymphomas and chronic myeloid leukaemia cell lines

Preparation method

This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

1-10 μM, 48 h, 37°C

Applications

S63845 is a small molecule MCL1 inhibitor with Ki < 1.2 nM. S63845 is effective against haematological cancer-derived cell lines. S63845 potently killed MCL1-dependent H929 multiple myeloma cells. S63845 disrupted binding of BAK and BAX to MCL1 in HeLa cells. Treatment with S63845 increased MCL1 protein levels in the HCT-116 colon carcinoma cell line. In the tested myeloma cell lines, some were highly sensitive to S63845 (IC50< 0.1 μM), six lines were moderately sensitive (0.1 μM < IC50 < 1 μM) and two lines were insensitive (IC50 > 1 μM). In a panel of human lymphomas and chronic myeloid leukaemia 11 cell lines: five lines were highly sensitive to S63845 (IC50 < 0.1 μM), three were moderately sensitive (0.1 μM < IC50< 1 μM) and three were insensitive to S63845 (IC50 >1 μM). In a panel of eight AML cell lines: all lines were sensitive to S63845 (IC50 4–233 nM) [1].

Animal experiment [1]:

Animal models

Human multiple myeloma (H929 and AMO1) xenografted mice

Dosage form

Intravenously injected (i.v.), 25 mg/kg

Application

Intravenously injected (i.v.) S63845 exerted dose-dependent anti-tumour activity in human multiple myeloma (H929 and AMO1) xenografts in immunocompromised mice, with maximal tumour growth inhibition (TGImax) of 114% in the AMO1 model and 103% in the H929 model. S63845 (25 mg/kg) induced complete regression in 7 out of 8 of the mice at 100 days after treatment in the AMO1 model. S63845 (i.v., 25 mg/kg, 5 days) cured 70% of immuno-competent C57BL/6 mice bearing Eμ-Myc mouse lymphomas, with no side-effects evident in normal tissues. S63845 (12.5 mg/kg) showed potent activity in the MV4-11 human AML xenograft model, with a TGImax of 86%. S63845 (25 mg/kg) resulted in completeremission in 6 out of 8 mice after 80 days.

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]. Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016 Oct 19;538(7626):477-482.

Background

S63845 is a small molecule MCL1 inhibitor with Ki < 1.2 nM [1].

Myeloid cell leukemia 1 (MCL1) is a pro-survival protein and belongs to BCL-2 family proteins. BCL-2 family proteins are key regulators of the mitochondrial apoptotic pathway. MCL1 is overexpressed in many cancers, so inhibitors targeting this protein may kills MCL1-dependent cancer cells [1].

S63845 is a highly selective and potent MCL1 inhibitor. S63845 bound human MCL1 with KD value of 0.19 nM. S63845 was approximately 1,000-fold more potent in killing MCL1-dependent H929 multiple myeloma cells than MCL1 inhibitor A-1210477. S63845 also induced caspase-dependent phosphatidyl-serine exposure, PARP cleavage and cytochrome c release from mitochondria. In HeLa cells, S63845 disrupted binding of BAK and BAX to MCL1. S63845 killed cancer cells through activation of the BAX/BAK-dependent mitochondrial apoptotic pathway by direct inhibition of MCL1 [1].

In immunocompromised mice with human multiple myeloma (H929 and AMO1) xenografts, intravenously injected (i.v.) S63845 showed dose-dependent anti-tumour activity with maximal tumour growth inhibition (TGImax) of 103% and 114% in the H929 and AMO1 model, respectively [1].

 

Reference:

1.Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016 Oct 19;538(7626):477-482.

Chemical Properties

Cas No. 1799633-27-4 SDF
Chemical Name (S)-2-(((S)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid
Canonical SMILES OC([C@@H](OC1=NC=NC2=C1[C@]([C@]3=C(C)C(Cl)=C(C=C3)OCCN4CCN(C)CC4)=C(C5=CC=C(F)O5)S2)CC6=CC=CC=C6OCC7=CC=NN7CC(F)(F)F)=O
Formula C39H37ClF4N6O6S M.Wt 829.26
Solubility ≥ 41.45mg/mL in DMSO, ≥ 20mg/mL in MeOH Storage 4°C, protect from light, stored under nitrogen
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 1.2059 mL 6.0295 mL 12.0589 mL
5 mM 0.2412 mL 1.2059 mL 2.4118 mL
10 mM 0.1206 mL 0.6029 mL 1.2059 mL
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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

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Average Rating: 5 ★★★★★ (Based on Reviews and 7 reference(s) in Google Scholar.)

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