BET inhibitor

Source: Wikipedia, the free encyclopedia.

BET inhibitors are a class of drugs that reversibly bind the

BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors.[1][2]

Discovery and development

NUT midline carcinoma.[7] Since this time a number of molecules have been described that are capable of targeting BET bromodomains.[8]

BET inhibitors have been described that are able to discriminate between the first and second bromodomains of BET proteins (BD1 vs BD2). However, no BET inhibitor has yet been described that can reliably distinguish between BET family members (BRD2 vs BRD3 vs BRD4 vs BRDT).[9] Only in the research context has targeting individual BET proteins been achieved by mutating them to be more sensitive to a derivative of JQ1 / I-BET 762.[10]

Mechanism of action

Interest in using BET inhibitors in cancer began with the observation that chromosomal translocations involving BET genes

NUT midline carcinoma. Subsequent research uncovered the dependence of some forms of acute myeloid leukemia,[11][12] multiple myeloma and acute lymphoblastic leukemia[13] on the BET protein BRD4, and the sensitivity of these cancers to BET inhibitors. In many cases, expression of the growth promoting transcription factor Myc is blocked by BET inhibitors.[14][15][16] BRD2 and BRD3 are functionally redundant and may be more important as therapeutic targets than is appreciated in studies depleting each BET protein individually.[17]
Recent studies also showed that BET inhibitors can be instrumental in overcoming resistance to other targeted therapies when used in combination therapies. Examples include use of BET inhibitors in combination with
BRAF-inhibitor (vemurafenib) for BRAF-inhibitor resistant melanomas carrying the BRAFV600E mutation.[18][19]

Specific BET inhibitors

BET inhibitors have been developed by publicly funded research labs as well as pharmaceutical companies including

GlaxoSmithKline, Oncoethix (purchased by Merck & Co. in 2014[20]), Oncoethix,[21] Constellation pharmaceuticals,[22] Resverlogix Corp[23] and Zenith epigenetics.[24]
Notable BET inhibitors include:

Targeting both BD1 and BD2 (bromodomains)

Selective targeting of BD1

Selective targeting of BD2

Dual kinase-bromodomain inhibitors

Bivalent BET inhibitors

See also

References

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  3. ^ JP application 2008156311, Umehara, Takashi; Tanaka, Akiko & Sato, Kazuhito et al., "BRD2 bromodomain binder", published 2008-07-10, assigned to RIKEN Institute of Physical and Chemical Research , since withdrawn.
  4. ^ JP 2623800, Naka, Yoichi; Ichiyanagi, Yukio & Haga, Keiichiro et al., "Thienodiazepine compounds", published 1997-06-25, assigned to Yoshitomi Pharmaceutical Co. 
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  14. ^ "Jay Bradner: Open-source cancer research | Talk Video". TED.com. 27 October 2011. Retrieved 2015-04-12.
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  20. ^ "Merck Acquires OncoEthix, a Privately Held Oncology Company Developing Novel BET Inhibitors for Hematological and Solid Cancers | Merck Newsroom Home". Mercknewsroom.com. 2014-12-18. Retrieved 2015-04-12.
  21. ^ "Site". Oncoethix. Retrieved 2015-04-12.
  22. ^ "Stellar Science, Breakthrough Medicine – Constellation Pharmaceuticals". Constellationpharma.com. Retrieved 2015-04-12.
  23. ^ "Home - Resverlogix Corp". Resverlogix.com. Retrieved 2015-05-05.
  24. ^ McLure KG (July 2014). "Developing Best in Class BET Inhibitors for Oncology & AI: from Discovery to the Clinic" (PDF). EpiCongress.
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  26. ^ GSK525762 clinical studies
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  28. ^ "Small molecule selective bromodomain inhibitors for treating cancer and other diseases". Tensha Therapeutics. Retrieved 2015-04-12.
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  30. ^ "Search of: bet inhibitor - List Results - ClinicalTrials.gov". ClinicalTrials.gov. Retrieved 1 June 2015.
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