Birabresib
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MedKoo CAT#: 206116

CAS#: 202590-98-5 (free base)

Description: Birabresib, also known as OTX015 and MK-8628, a potent BET bromodomian inhibitor, which targets the BET bromodomain proteins 2, 3, and 4 (BRD2/3/4). BRDs 2, 3, and 4 are considered potential cancer targets because of their pivotal role in regulating the transcription of growth-promoting genes and cell cycle regulators. OTX015 is the first BRD2/3/4 inhibitor to enter clinical trials. OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240 nmol/L, without significant differences among the different histotypes.


Chemical Structure

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Birabresib
CAS# 202590-98-5 (free base)

Theoretical Analysis

MedKoo Cat#: 206116
Name: Birabresib
CAS#: 202590-98-5 (free base)
Chemical Formula: C25H22ClN5O2S
Exact Mass: 491.11827
Molecular Weight: 491.99248
Elemental Analysis: C, 61.03; H, 4.51; Cl, 7.21; N, 14.23; O, 6.50; S, 6.52

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 850.0 Ready to ship
500.0mg USD 1650.0 Ready to ship
1.0g USD 2650.0 Ready to ship
2.0g USD 4250.0 2 Weeks
5.0g USD 7850.0 2 Weeks
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Related CAS #: 204587-26-8 (dihydrate); 202590-98-5 (free base)  

Synonym: OTX015; OTX-015; OTX 015; MK-8628; MK 8628; MK8628; Birabresib.

IUPAC/Chemical Name: (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide.

InChi Key: GNMUEVRJHCWKTO-FQEVSTJZSA-N

InChi Code: 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

SMILES Code: O=C(NC1=CC=C(O)C=C1)C[C@H]2C3=NN=C(C)N3C4=C(C(C)=C(C)S4)C(C5=CC=C(Cl)C=C5)=N2

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Birabresib (OTX-015) is a bromodomain (BRD2/3/4) inhibitor with IC50s ranging from 92 to 112 nM.
In vitro activity: Naïve and memory murine and human CD4+ T cells were exposed to varying concentrations of OTX015 in vitro, and its impact on cytokine expression was quantified by flow cytometry. OTX015 suppressed both murine and human CD4+ T cell proliferation. Its impact on cytokine expression varied in murine and human naïve and memory subsets. OTX015 was similarly effective as JQ1, a previously studied BET inhibitor that was used as the control, in the suppression of cytokines and T helper cell proliferation. Higher concentrations of OTX015 also had a greater impact on the viability of murine versus human cells. IL-17 and IFN-γ expression was not altered in murine memory CD4+ T cells, whereas in human memory CD4+ T cells, OTX015 inhibited IL-17, but not IFN-γ. Across all human T cell subsets OTX015 suppressed IL-17 more effectively than IFN-γ. Reference: Curr Mol Med. 2018;18(9):594-601. https://www.eurekaselect.com/169393/article
In vivo activity: Oral administration of the bromodomain inhibitor OTX015 displayed significant antitumor activity in a mouse model of disseminated human myeloma. OTX015 promoted osteoblast differentiation of mesenchymal stem cells (MSCs) and inhibited osteoclast formation and resorption in vivo experiments. Reference: Mol Pharm. 2018 Sep 4;15(9):4139-4147. https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b00554

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 73.5 149.39
Ethanol 98.0 199.19

Preparing Stock Solutions

The following data is based on the product molecular weight 491.99248 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Hu X, Schewitz-Bowers LP, Lait PJP, Copland DA, Stimpson ML, Li JJ, Liu Y, Dick AD, Lee RWJ, Wei L. The Bromodomain and Extra-Terminal Protein Inhibitor OTX015 Suppresses T Helper Cell Proliferation and Differentiation. Curr Mol Med. 2018;18(9):594-601. doi: 10.2174/1566524019666190126112238. PMID: 30683020. 2. Vázquez R, Riveiro ME, Astorgues-Xerri L, Odore E, Rezai K, Erba E, Panini N, Rinaldi A, Kwee I, Beltrame L, Bekradda M, Cvitkovic E, Bertoni F, Frapolli R, D'Incalci M. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget. 2017 Jan 31;8(5):7598-7613. doi: 10.18632/oncotarget.13814. PMID: 27935867; PMCID: PMC5352346. 3. Shi J, Song S, Han H, Xu H, Huang M, Qian C, Zhang X, Ouyang L, Hong Y, Zhuang W, Li B. Potent Activity of the Bromodomain Inhibitor OTX015 in Multiple Myeloma. Mol Pharm. 2018 Sep 4;15(9):4139-4147. doi: 10.1021/acs.molpharmaceut.8b00554. Epub 2018 Aug 9. PMID: 30048594.
In vitro protocol: 1. Hu X, Schewitz-Bowers LP, Lait PJP, Copland DA, Stimpson ML, Li JJ, Liu Y, Dick AD, Lee RWJ, Wei L. The Bromodomain and Extra-Terminal Protein Inhibitor OTX015 Suppresses T Helper Cell Proliferation and Differentiation. Curr Mol Med. 2018;18(9):594-601. doi: 10.2174/1566524019666190126112238. PMID: 30683020. 2. Vázquez R, Riveiro ME, Astorgues-Xerri L, Odore E, Rezai K, Erba E, Panini N, Rinaldi A, Kwee I, Beltrame L, Bekradda M, Cvitkovic E, Bertoni F, Frapolli R, D'Incalci M. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget. 2017 Jan 31;8(5):7598-7613. doi: 10.18632/oncotarget.13814. PMID: 27935867; PMCID: PMC5352346.
In vivo protocol: 1. Vázquez R, Licandro SA, Astorgues-Xerri L, Lettera E, Panini N, Romano M, Erba E, Ubezio P, Bello E, Libener R, Orecchia S, Grosso F, Riveiro ME, Cvitkovic E, Bekradda M, D'Incalci M, Frapolli R. Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts. Int J Cancer. 2017 Jan 1;140(1):197-207. doi: 10.1002/ijc.30412. Epub 2016 Sep 19. PMID: 27594045. 2. Shi J, Song S, Han H, Xu H, Huang M, Qian C, Zhang X, Ouyang L, Hong Y, Zhuang W, Li B. Potent Activity of the Bromodomain Inhibitor OTX015 in Multiple Myeloma. Mol Pharm. 2018 Sep 4;15(9):4139-4147. doi: 10.1021/acs.molpharmaceut.8b00554. Epub 2018 Aug 9. PMID: 30048594.

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1: Boi M, Todaro M, Vurchio V, Yang SN, Moon J, Kwee I, Rinaldi A, Pan H, Crescenzo R, Cheng M, Cerchietti L, Elemento O, Riveiro ME, Cvitkovic E, Bertoni F, Inghirami G; AIRC 5xMille Consortium ‘Genetics-Driven Targeted Management of Lymphoid Malignancies’.. Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes. Oncotarget. 2016 Nov 29;7(48):79637-79653. doi: 10.18632/oncotarget.12876. PubMed PMID: 27793034.

2: Vázquez R, Riveiro ME, Astorgues-Xerri L, Odore E, Rezai K, Erba E, Panini N, Rinaldi A, Kwee I, Beltrame L, Bekradda M, Cvitkovic E, Bertoni F, Frapolli R, D'Incalci M. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget. 2016 Dec 7. doi: 10.18632/oncotarget.13814. [Epub ahead of print] PubMed PMID: 27935867.

3: Coudé MM, Braun T, Berrou J, Dupont M, Bertrand S, Masse A, Raffoux E, Itzykson R, Delord M, Riveiro ME, Herait P, Baruchel A, Dombret H, Gardin C. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015 Jul 10;6(19):17698-712. PubMed PMID: 25989842; PubMed Central PMCID: PMC4627339.

4: Riveiro ME, Astorgues-Xerri L, Vazquez R, Frapolli R, Kwee I, Rinaldi A, Odore E, Rezai K, Bekradda M, Inghirami G, D'Incalci M, Noel K, Cvitkovic E, Raymond E, Bertoni F. OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations. Oncotarget. 2016 Dec 20;7(51):84675-84687. doi: 10.18632/oncotarget.13181. PubMed PMID: 27835869.

5: Berenguer-Daizé C, Astorgues-Xerri L, Odore E, Cayol M, Cvitkovic E, Noel K, Bekradda M, MacKenzie S, Rezai K, Lokiec F, Riveiro ME, Ouafik L. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int J Cancer. 2016 Nov 1;139(9):2047-55. doi: 10.1002/ijc.30256. PubMed PMID: 27388964.

6: Amorim S, Stathis A, Gleeson M, Iyengar S, Magarotto V, Leleu X, Morschhauser F, Karlin L, Broussais F, Rezai K, Herait P, Kahatt C, Lokiec F, Salles G, Facon T, Palumbo A, Cunningham D, Zucca E, Thieblemont C. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016 Apr;3(4):e196-204. doi: 10.1016/S2352-3026(16)00021-1. PubMed PMID: 27063978.

7: Odore E, Lokiec F, Cvitkovic E, Bekradda M, Herait P, Bourdel F, Kahatt C, Raffoux E, Stathis A, Thieblemont C, Quesnel B, Cunningham D, Riveiro ME, Rezaï K. Phase I Population Pharmacokinetic Assessment of the Oral Bromodomain Inhibitor OTX015 in Patients with Haematologic Malignancies. Clin Pharmacokinet. 2016 Mar;55(3):397-405. doi: 10.1007/s40262-015-0327-6. PubMed PMID: 26341814.

8: Balaji N, Chinnapattu M, Dixit A, Sahu P, P S S, Mullangi R. Validation of an enantioselective LC-MS/MS method to quantify enantiomers of (±)-OTX015 in mice plasma: Lack of in vivo inversion of (-)-OTX015 to its antipode. Biomed Chromatogr. 2016 Sep 16. doi: 10.1002/bmc.3853. [Epub ahead of print] PubMed PMID: 27632936.

9: Boi M, Gaudio E, Bonetti P, Kwee I, Bernasconi E, Tarantelli C, Rinaldi A, Testoni M, Cascione L, Ponzoni M, Mensah AA, Stathis A, Stussi G, Riveiro ME, Herait P, Inghirami G, Cvitkovic E, Zucca E, Bertoni F. The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs. Clin Cancer Res. 2015 Apr 1;21(7):1628-38. doi: 10.1158/1078-0432.CCR-14-1561. PubMed PMID: 25623213.

10: Berthon C, Raffoux E, Thomas X, Vey N, Gomez-Roca C, Yee K, Taussig DC, Rezai K, Roumier C, Herait P, Kahatt C, Quesnel B, Michallet M, Recher C, Lokiec F, Preudhomme C, Dombret H. Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol. 2016 Apr;3(4):e186-95. doi: 10.1016/S2352-3026(15)00247-1. PubMed PMID: 27063977.

11: Vázquez R, Licandro SA, Astorgues-Xerri L, Lettera E, Panini N, Romano M, Erba E, Ubezio P, Bello E, Libener R, Orecchia S, Grosso F, Riveiro ME, Cvitkovic E, Bekradda M, D'Incalci M, Frapolli R. Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts. Int J Cancer. 2017 Jan 1;140(1):197-207. doi: 10.1002/ijc.30412. PubMed PMID: 27594045.

12: Gaudio E, Tarantelli C, Ponzoni M, Odore E, Rezai K, Bernasconi E, Cascione L, Rinaldi A, Stathis A, Riveiro E, Cvitkovic E, Zucca E, Bertoni F. Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma. Oncotarget. 2016 Sep 6;7(36):58142-58147. doi: 10.18632/oncotarget.10983. PubMed PMID: 27494885; PubMed Central PMCID: PMC5295419.

13: Lu P, Qu X, Shen Y, Jiang Z, Wang P, Zeng H, Ji H, Deng J, Yang X, Li X, Lu H, Zhu H. The BET inhibitor OTX015 reactivates latent HIV-1 through P-TEFb. Sci Rep. 2016 Apr 12;6:24100. doi: 10.1038/srep24100. PubMed PMID: 27067814; PubMed Central PMCID: PMC4828723.

14: Stathis A, Zucca E, Bekradda M, Gomez-Roca C, Delord JP, de La Motte Rouge T, Uro-Coste E, de Braud F, Pelosi G, French CA. Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628. Cancer Discov. 2016 May;6(5):492-500. doi: 10.1158/2159-8290.CD-15-1335. PubMed PMID: 26976114; PubMed Central PMCID: PMC4854801.

15: Henssen A, Althoff K, Odersky A, Beckers A, Koche R, Speleman F, Schäfers S, Bell E, Nortmeyer M, Westermann F, De Preter K, Florin A, Heukamp L, Spruessel A, Astrahanseff K, Lindner S, Sadowski N, Schramm A, Astorgues-Xerri L, Riveiro ME, Eggert A, Cvitkovic E, Schulte JH. Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition. Clin Cancer Res. 2016 May 15;22(10):2470-81. doi: 10.1158/1078-0432.CCR-15-1449. PubMed PMID: 26631615.

16: Saenz DT, Fiskus W, Qian Y, Manshouri T, Rajapakshe K, Raina K, Coleman KG, Crew AP, Shen A, Mill CP, Sun B, Qiu P, Kadia TM, Pemmaraju N, DiNardo C, Kim MS, Nowak AJ, Coarfa C, Crews CM, Verstovsek S, Bhalla KN. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017 Jan 31. doi: 10.1038/leu.2016.393. [Epub ahead of print] PubMed PMID: 28042144.

17: Asangani IA, Wilder-Romans K, Dommeti VL, Krishnamurthy PM, Apel IJ, Escara-Wilke J, Plymate SR, Navone NM, Wang S, Feng FY, Chinnaiyan AM. BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer. Mol Cancer Res. 2016 Apr;14(4):324-31. doi: 10.1158/1541-7786.MCR-15-0472. PubMed PMID: 26792867; PubMed Central PMCID: PMC4834259.

18: Lin X, Huang X, Uziel T, Hessler P, Albert DH, Roberts-Rapp LA, McDaniel KF, Kati WM, Shen Y. HEXIM1 as a Robust Pharmacodynamic Marker for Monitoring Target Engagement of BET Family Bromodomain Inhibitors in Tumors and Surrogate Tissues. Mol Cancer Ther. 2017 Feb;16(2):388-396. doi: 10.1158/1535-7163.MCT-16-0475. PubMed PMID: 27903752.

19: Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K, Crews CM. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem Biol. 2015 Jun 18;22(6):755-63. doi: 10.1016/j.chembiol.2015.05.009. PubMed PMID: 26051217; PubMed Central PMCID: PMC4475452.

20: Pérez-Peña J, Serrano-Heras G, Montero JC, Corrales-Sánchez V, Pandiella A, Ocaña A. In Silico Analysis Guides Selection of BET Inhibitors for Triple-Negative Breast Cancer Treatment. Mol Cancer Ther. 2016 Aug;15(8):1823-33. doi: 10.1158/1535-7163.MCT-16-0004. PubMed PMID: 27256375.



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