OTX015 （MK 8628/Birabresib）

Catalog No.S7360

OTX015 （MK 8628/Birabresib） Chemical Structure

Molecular Weight(MW): 491.99

OTX015 is a potent BET bromodomain inhibitor with EC50 ranging from 10 to 19 nM for BRD2, BRD3, and BRD4 in cell-free assays. Phase 1.

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Cited by 11 Publications

4 Customer Reviews

  • A. Growth inhibition IC50 values of CUDC-907 and three BET inhibitors (I-BET-762, JQ1, and OTX015) in three BRD–NUT fusion-positive NMC cell lines. Cell viability after 72-hour incubation was assessed by the CellTiter-Glo assay. Growth inhibition IC50 values for each compound were determined by GraphPad Prism 5.

    Mol Cancer Ther, 2016, 16(4 suppl 1):S263-S276. OTX015 （MK 8628/Birabresib） purchased from Selleck.

    F, Representative histologic images of the individual treatments of the xenografts performed in C. Slides were stained with hematoxylin and eosin (HE).

    Clin Cancer Res, 2018, doi: 10.1158/1078-0432.CCR-18-1040. OTX015 （MK 8628/Birabresib） purchased from Selleck.

  • LN229, U87, NCH644, or GBM14 cells were treated with indicated drugs and analyzed for levels of the indicated proteins by conventional Western blotting or capillary electrophoresis. All concentrations are in μmol/L. Blots or capillary electrophoresis were quantified for the levels of Mcl-1 and Noxa normalized with its related loading control.

    Clin Cancer Res, 2018, 24(16):3941-3954. OTX015 （MK 8628/Birabresib） purchased from Selleck.

    C11 cells were mock-treated or treated with either OTX015 (0.01 μM), prostratin (0.2 μM), or OTX015 (0.01 μM)/prostratin (0.2 μM). The effect of activation of the HIV-1 promoter was determined by quantifying GFP-positive cells 48 hours after treatment using flow cytometry. A summary of the activation assays is presented as a series of histograms.

    Sci Rep, 2016, 6:24100. OTX015 （MK 8628/Birabresib） purchased from Selleck.

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Biological Activity

Description OTX015 is a potent BET bromodomain inhibitor with EC50 ranging from 10 to 19 nM for BRD2, BRD3, and BRD4 in cell-free assays. Phase 1.
Features Orally bioavailable BRD2/3/4-selective inhibitor that has been tested in Phase I clinical trials for treatment of Haematological Malignancies.
Targets
BRDs [1]
(Cell-free assay)
10-19 nM(EC50)
In vitro

OTX015 inhibits the binding of BRD2, BRD3, and BRD4 to AcH4 with IC50 ranging from 92 to 112 nM, and inhibits the growth of a variety of human cancer cell lines with GI50 ranging from 60 to 200 nM. [1] OTX015 results in rapid down-regulation of c-MYC expression, and show the synergistic anti-proliferative effects in combination with ALK inhibitors in ALKpos ALCL cell lines. [2]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Rosetta2 DE3 cells MX\GeY5kfGmxbjDhd5NigQ>? NV3tRmNwOzBibXnudy=> MlmySIl{eGyjY3Xt[Y51KG:oIF\BUU1t[WKnbHXkJHpDSTJ2ODDmdo9uKEKUREOgRmQzKCh|ME[geI8hPDF5IHHtbY5wKGGlaXSgdoV{cWS3ZYOpJEh2dmuwb4fuJI9zcWerbjmg[ZhxemW|c3XkJIlvKFKxc3X0eIEzKESHMzDj[YxteyCjZoTldkA{OCCvaX7zJIJ6KG[udX;y[ZNk\W6lZTDwc4xiemm8YYTpc44h[XO|YYmsJGtqRTRibl2= M4PJSFI3ODhyME[0

... Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Western blot
BRD4; 

PubMed: 26051217     


Small molecule BRD4 inhibitors lead to significant BRD4 accumulation. Namalwa and Ramos cells were treated overnight with increasing doses of JQ1 and OTX015. Lysates were collected and subjected to immunoblot analysis with antibodies for BRD4 and actin.

c-Myc; 

PubMed: 26051217     


Small molecule BRD4 inhibitors lead to downstream c-MYC suppression, but not efficiently. Namalwa cells were treated overnight with increasing doses of JQ1 and OTX015, lysates were collected and analyzed by immunoblot with antibodies for c-MYC and actin.

JAK2 / p-STAT5 / STAT5 / p-STAT3 / c-Myc / PIM1 / CDK6 / HEXIM1 / p27 / p21 / Bcl-xL / γH2AX; 

PubMed: 28042144     


SET-2 cells were treated with the indicated concentrations of ARV-825 or OTX015 for 18 hours. Total cell lysates were prepared and immunoblot analyses were conducted as indicated. The expression levels of β-Actin in the cell lysates served as the loading 䲧疝Ỵ疞

ZO-1 / Vimentin; 

PubMed: 27980063     


JQ1/OTX015 treatment results in decreased expression of the epithelial marker ZO-1 and an increase in mesenchymal marker Vimentin as shown by Western blot analyses of whole cell protein lysates.

26051217 28042144 27980063
Immunofluorescence
BRD4 ; 

PubMed: 28042144     


SET2 cells were treated with the indicated concentrations of ARV-825 or OTX015 for 16 hours. Then, cells were cytospun onto glass slides and immunostained for BRD4 expression. Cells were counterstained with DAPI and images were acquired utilizing confocal䲧疝Ỵ疞㧀疜膉痘 瘿뙠ෆᾰƌෆĀ 㺣痖

Vimentin; 

PubMed: 27980063     


Immunofluorescence staining of Vimentin following JQ1/OTX015 treatment confirms a decreased epithelial phenotype.

28042144 27980063
In vivo OTX015 (p.o.) significantly inhibits the growth of Ty82 BRD-NUT midline carcinoma tumors in nude mice by 79% at 100 mg/kg qd and 61% at 10 mg/kg bid, respectively. [1]

Protocol

Kinase Assay:

[1]
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TR-FRET Assay [1]:

To assess binding of OTX015 to BRD2, BRD3, and BRD4, BRD-expressing CHO cell lysate (from CHO cells transfected with expression plasmids for Flag-tagged BRD2, BRD3, or BRD4 or vector alone), europium-conjugated anti-Flag antibody, XL-665-conjugated streptavidin, and biotinylated OTX015 are incubated at room temperature for 0.2 to 2 h. Fluorescence is measured by TR-FRET using an EnVision 2103 Multilabel Reader and EC50 for binding is calculated by nonlinear regression using PRISM version 5.02.
Cell Research:

[1]
+ Expand
  • Cell lines: Human tumor cells
  • Concentrations: ~2 μM
  • Incubation Time: 72 hours
  • Method:

    Effects of OTX015 on cancer cell proliferation are evaluated by incubating human tumor cells for 72 h with increasing concentrations of OTX015 and assessing proliferation using a tetrazolium salt (WST-8)-based colorimetric assay.


    (Only for Reference)
Animal Research:

[1]
+ Expand
  • Animal Models: BLAB/c-nu/nu mice bearing established Ty82 BRD-NUT midline carcinoma xenografts.
  • Formulation: --
  • Dosages: ~100 mg/kg
  • Administration: p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 98 mg/mL (199.19 mM)
Ethanol 98 mg/mL (199.19 mM)
Water Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+30% PEG 300+5% Tween 80+ddH2O
For best results, use promptly after mixing. 		5mg/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

Molecular Weight 491.99
Formula

C25H22ClN5O2S
CAS No. 202590-98-5
Storage powder
in solvent
Synonyms N/A

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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.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID