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birabresib   Click here for help

GtoPdb Ligand ID: 8359

Synonyms: MK-8628 | OTX-015 | OTX015
PDB Ligand
Compound class: Synthetic organic
Comment: OTX015 inhibits interaction between bromodomain and extra-terminal (BET) family of bromodomain-containing proteins (BRDs) BET domains and acetylated histone 4 (AcH4). It is an orally available novel BRD2/3/4 inhibitor with potent preclinical anti-tumour activity [1,4,6,10,12-13]. OTX015 is an analogue of (+)-JQ1.

birabresib is commercially available from our sponsors

2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 5
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 120.12
Molecular weight 491.12
XLogP 5.74
No. Lipinski's rules broken 1

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES O=C(CC1N=C(c2ccc(cc2)Cl)c2c(n3c1nnc3C)sc(c2C)C)Nc1ccc(cc1)O
Isomeric SMILES O=C(C[C@@H]1N=C(c2ccc(cc2)Cl)c2c(n3c1nnc3C)sc(c2C)C)Nc1ccc(cc1)O
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
InChI Key GNMUEVRJHCWKTO-FQEVSTJZSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Berenguer-Daizé C, Astorgues-Xerri L, Odore E, Cayol M, Cvitkovic E, Noel K, Bekradda M, MacKenzie S, Rezai K, Lokiec F et al.. (2016)
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, 139 (9): 2047-55. [PMID:27388964]
2. Berthon C, Raffoux E, Thomas X, Vey N, Gomez-Roca C, Yee K, Taussig DC, Rezai K, Roumier C, Herait P et al.. (2016)
Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study.
Lancet Haematol, 3 (4): e186-95. [PMID:27063977]
3. Boi M, Gaudio E, Bonetti P, Kwee I, Bernasconi E, Tarantelli C, Rinaldi A, Testoni M, Cascione L, Ponzoni M et al.. (2015)
The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs.
Clin Cancer Res, 21 (7): 1628-38. [PMID:25623213]
4. Boi M, Todaro M, Vurchio V, Yang SN, Moon J, Kwee I, Rinaldi A, Pan H, Crescenzo R, Cheng M et al.. (2016)
Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes.
Oncotarget, 7 (48): 79637-79653. [PMID:27793034]
5. Filippakopoulos P, Knapp S. (2014)
Targeting bromodomains: epigenetic readers of lysine acetylation.
Nat Rev Drug Discov, 13 (5): 337-56. [PMID:24751816]
6. Gaudio E, Tarantelli C, Ponzoni M, Odore E, Rezai K, Bernasconi E, Cascione L, Rinaldi A, Stathis A, Riveiro E et al.. (2016)
Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma.
Oncotarget, 7 (36): 58142-58147. [PMID:27494885]
7. Hattori N, Ushijima T. (2014)
Compendium of aberrant DNA methylation and histone modifications in cancer.
Biochem Biophys Res Commun, 455 (1-2): 3-9. [PMID:25194808]
8. Noel JK, Iwata K, Ooike S, Sugahara K, Nakamura H and Daibata M. 
Abstract C244: Development of the BET bromodomain inhibitor OTX015.
Accessed on 07/05/2015. Modified on 07/05/2015. aacrjournals.org, http://mct.aacrjournals.org/content/12/11_Supplement/C244.short
9. Odore E, Lokiec F, Cvitkovic E, Bekradda M, Herait P, Bourdel F, Kahatt C, Raffoux E, Stathis A, Thieblemont C et al.. (2016)
Phase I Population Pharmacokinetic Assessment of the Oral Bromodomain Inhibitor OTX015 in Patients with Haematologic Malignancies.
Clin Pharmacokinet, 55 (3): 397-405. [PMID:26341814]
10. Riveiro ME, Astorgues-Xerri L, Vazquez R, Frapolli R, Kwee I, Rinaldi A, Odore E, Rezai K, Bekradda M, Inghirami G et al.. (2016)
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, 7 (51): 84675-84687. [PMID:27835869]
11. Rosner M, Hengstschläger M. (2012)
Targeting epigenetic readers in cancer.
N Engl J Med, 367 (18): 1764-5. [PMID:23113498]
12. Vázquez R, Licandro SA, Astorgues-Xerri L, Lettera E, Panini N, Romano M, Erba E, Ubezio P, Bello E, Libener R et al.. (2017)
Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts.
Int J Cancer, 140 (1): 197-207. [PMID:27594045]
13. Vázquez R, Riveiro ME, Astorgues-Xerri L, Odore E, Rezai K, Erba E, Panini N, Rinaldi A, Kwee I, Beltrame L et al.. (2017)
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, 8 (5): 7598-7613. [PMID:27935867]