OTX-015

BRD inhibitor CAS# 202590-98-5

OTX-015

2D Structure

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OTX-015

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Chemical Properties of OTX-015

Cas No. 202590-98-5 SDF Download SDF
PubChem ID 9936746 Appearance Powder
Formula C25H22ClN5O2S M.Wt 491.99
Type of Compound N/A Storage Desiccate at -20°C
Synonyms MK-8628; Birabresib
Solubility DMSO : ≥ 49 mg/mL (99.60 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
SMILES CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)NC4=CC=C(C=C4)O)C5=CC=C(C=C5)Cl)C
Standard InChIKey GNMUEVRJHCWKTO-FQEVSTJZSA-N
Standard InChI InChI=1S/C25H22ClN5O2S/c1-13-14(2)34-25-22(13)23(16-4-6-17(26)7-5-16)28-20(24-30-29-15(3)31(24)25)12-21(33)27-18-8-10-19(32)11-9-18/h4-11,20,32H,12H2,1-3H3,(H,27,33)/t20-/m0/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 OTX-015

DescriptionOTX-015 is an orally bioavailable and small molecule inhibitor of bromodomain and extra terminal domain (BET) family proteins with EC50 values of 10-19 nM for BRD2, BRD3, and BRD4.
TargetsBRD2BRD3BRD4   

Protocol

Kinase experiment [1]:

Binding assays

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 were incubated at room temperature for 0.2 to 2h. Fluorescence was measured by TR-FRET using an EnVision 2103 Multilabel Reader and EC50 for binding was calculated by nonlinear regression using PRISM version 5.02. Using a similar system, the effect of OTX015 on binding of BRD2, BRD3, and BRD4 to acetylated histone H4 (AcH4) was evaluated by incubating biotin-conjugated -AcH4, BRD-expressing CHO cell lysate, europium-conjugated anti-Flag antibody, and XL-665-conjugated streptavidin. Fluorescence was measured by TR-FRET using an EnVision 2103 Multilabel Reader and percent binding was calculated by defining the value of the sample without biotin conjugate dAcH4 as 0% and the sample without OTX015 as 100%. The IC50 value was calculated by nonlinear regression using PRISM version 5.02.

Cell experiment [1]:

Cell lines

Human tumor cells

Preparation method

Soluble in DMSO > 10 mM. 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

72 h.

Applications

OTX-015 inhibits the growth of a variety of human cancer cell lines. OTX-015 exhibits growth inhibition with GI50 values of 60-200 nM for most hematologic malignancies tested.

Animal experiment [1]:

Animal models

BLAB/c-nu/nu mice bearing established Ty82 BRD-NUT midline carcinoma xenografts.

Dosage form

0, 10, 30 or 100 mg/kg qd or 10 mg/kg bid; 14 days; oral gavage.

Application

OTX-015 significantly inhibits tumor growth and exhibits TGI by 79% and 61% at 100 mg/kg qd and 10 mg/kg bid.

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]. J. Kay Noel, Kazunori Iwata, Shinsuke Ooike, et al. Development of the BET bromodomain inhibitor OTX015 [J]. Mol Cancer Ther, 2013, 12(11 Suppl): C244.

OTX-015 Dilution Calculator

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Preparing Stock Solutions of OTX-015

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0326 mL 10.1628 mL 20.3256 mL 40.6512 mL 50.814 mL
5 mM 0.4065 mL 2.0326 mL 4.0651 mL 8.1302 mL 10.1628 mL
10 mM 0.2033 mL 1.0163 mL 2.0326 mL 4.0651 mL 5.0814 mL
50 mM 0.0407 mL 0.2033 mL 0.4065 mL 0.813 mL 1.0163 mL
100 mM 0.0203 mL 0.1016 mL 0.2033 mL 0.4065 mL 0.5081 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 OTX-015

OTX-015 is a potent inhibitor of BRD2, BRD3, and BRD4 with IC50 values range from 92 to 112 nM [1].
BRD2, BRD3, and BRD4 belong to BET bromodomain family and play an important role in regulating transcription. BRDs regulate several oncogenes transcription in a variety of cancers and thus have emerged as a promising target [2].
OTX-015 is a selective BRD2, BRD3, and BRD4 inhibitor and inhibits the binding of BRD2, BRD3, and BRD4 to AcH4. Using TR-FRET method and CHO cell lysate harboring BRD2, BRD3, and BRD4 to research the effect of OTX-015, result showed that OTX-015 inhibited BET family binding to AcH4 in a dose-dependent manner and the EC50 values range from 10 to 19 nM. When tested with human tumor cell lines, incubation with OTX-015 for 72 hours inhibited cell proliferation with GI 50 values ranged from 60 to 200 nM [1]. In ALKpos ALCL cell lines, treatment of OTX-015 for 24 h arrested cell proliferation in G1 phase which was more pronounced at 48 h and 72 h, and tested with SUPM2/TS and JB-6 cell lines OTX-015 showed ability to increase cell death rate [3].
In BLAB/c-nu/nu mice model with established Ty82 BRD-NUT midline carcinoma xenografts, oral administration of OTX-015 markedly inhibited tumor growth and reduced tumor volume [1].
References:
[1]. J. Kay Noel, Kazunori Iwata, Shinsuke Ooike, et al. Development of the BET bromodomain inhibitor OTX015 [J]. Mol Cancer Ther November 2013 12; C244.
[2]. Fu LL, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery [J]. Oncotarget. 2015 Mar 20;6(8):5501-5516.
[3]. Michela Boi, Maria Todaro, Valentina Vurchio, et al. OTX015, a bromodomain and extraterminal inhibitor, represents a novel agent for ALK positive anaplastic large cell lymphoma [J]. Mol Cancer Ther November 2013 12; A219.

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References on OTX-015

Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents.[Pubmed:27607580]

Cell Death Dis. 2016 Sep 8;7(9):e2365.

Non-small cell lung cancer (NSCLC) has the highest incidence of cancer-related death worldwide and a high medical need for more effective therapies. Small-molecule inhibitors of the bromodomain and extra terminal domain (BET) family such as JQ1, I-BET762 and OTX-015 are active in a wide range of different cancer types, including lung cancer. Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the effects of BET inhibition on the apoptotic pathway remain largely unknown. Here we evaluated the activity of BET bromodomain inhibitors on cell cycle distribution and on components of the apoptosis response. Using a panel of 12 KRAS-mutated NSCLC models, we found that cell lines responsive to BET inhibitors underwent apoptosis and reduced their S-phase population, concomitant with downregulation of c-Myc expression. Conversely, ectopic c-Myc overexpression rescued the anti-proliferative effect of JQ1. In the H1373 xenograft model, treatment with JQ1 significantly reduced tumor growth and downregulated the expression of c-Myc. The effects of BET inhibition on the expression of 370 genes involved in apoptosis were compared in sensitive and resistant cells and we found the expression of the two key apoptosis regulators FLIP and XIAP to be highly BET dependent. Consistent with this, combination treatment of JQ1 with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the pro-apoptotic chemotherapeutic agent cisplatin enhanced induction of apoptosis in both BET inhibitor sensitive and resistant cells. Further we showed that combination of JQ1 with cisplatin led to significantly improved anti-tumor efficacy in A549 tumor-bearing mice. Altogether, these results show that the identification of BET-dependent genes provides guidance for the choice of drug combinations in cancer treatment. They also demonstrate that BET inhibition primes NSCLC cells for induction of apoptosis and that a combination with pro-apoptotic compounds represents a valuable strategy to overcome treatment resistance.

Description

Birabresib (OTX-015) is a potent bromodomain (BRD2/3/4) inhibitor with IC50s ranging from 92 to 112 nM.

Keywords:

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