BET inhibitor explained

BET inhibitors are a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors.[1] [2]

Discovery and development

Thienodiazepine BET inhibitors were discovered in a phenotypic drug screen by scientists at Yoshitomi Pharmaceuticals (now Mitsubishi Tanabe Pharma) in the early 1990s, and their potential both as anti-inflammatories and anti-cancer agents noted.[3] [4] OncoEthix (acquired by Merck in 2014) in-licensed OTX-015 from Mitsubishi and in 2012 initiated the first BET inhibitor clinical trial for oncology (ClinicalTrials.gov Identifier: NCT01713582). BET inhibitors were also independently discovered in phenotypic screens for small molecule inducers of Apolipoprotein A-I by both GSK and Resverlogix.[5] [6] In 2010 the use of JQ1, a tert-butyl synthetic precursor of OTX-015, was published having activity in vitro in 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 BRD3 and BRD4 drove the pathogenesis of the rare cancer 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 γ-secretase inhibitors for T cell acute lymphoblastic leukemia and 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

Notes and References

  1. Garnier JM, Sharp PP, Burns CJ . BET bromodomain inhibitors: a patent review . Expert Opinion on Therapeutic Patents . 24 . 2 . 185–99 . February 2014 . 24261714 . 10.1517/13543776.2014.859244 . 24647727 .
  2. Shi J, Vakoc CR . The mechanisms behind the therapeutic activity of BET bromodomain inhibition . Molecular Cell . 54 . 5 . 728–36 . June 2014 . 24905006 . 4236231 . 10.1016/j.molcel.2014.05.016 .
  3. JP. 2008156311. 2008-07-10. BRD2 bromodomain binder. RIKEN Institute of Physical and Chemical Research. Umehara. Takashi. Tanaka. Akiko. Sato. Kazuhito. Yokoyama. Shigeyuki. application., since withdrawn.
  4. JP. 2623800. 1997-06-25. Thienodiazepine compounds. Yoshitomi Pharmaceutical Co.. Naka. Yoichi. Ichiyanagi. Yukio. Haga. Keiichiro. Hosoya. Shinko.
  5. Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A . Suppression of inflammation by a synthetic histone mimic . Nature . 468 . 7327 . 1119–23 . December 2010 . 21068722 . 10.1038/nature09589 . 5415086 . 2010Natur.468.1119N .
  6. McLure KG, Gesner EM, Tsujikawa L, Kharenko OA, Atwell S, Campeau E, Wasiak S, Stein A, White A, Fontano E, Suto RK, Wong NC, Wagner GS, Hansen HC, Young PR . RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist . PLOS ONE . 8 . 12 . e83190 . December 2013 . 24391744 . 10.1371/journal.pone.0083190 . 3877016 . free .
  7. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE . Selective inhibition of BET bromodomains . Nature . 468 . 7327 . 1067–73 . December 2010 . 20871596 . 3010259 . 10.1038/nature09504 . 2010Natur.468.1067F .
  8. Picaud S, Da Costa D, Thanasopoulou A, Filippakopoulos P, Fish PV, Philpott M, Fedorov O, Brennan P, Bunnage ME, Owen DR, Bradner JE, Taniere P, O'Sullivan B, Müller S, Schwaller J, Stankovic T, Knapp S . PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains . Cancer Research . 73 . 11 . 3336–46 . June 2013 . 23576556 . 3673830 . 10.1158/0008-5472.CAN-12-3292 .
  9. Filippakopoulos P, Knapp S . Targeting bromodomains: epigenetic readers of lysine acetylation . Nature Reviews. Drug Discovery . 13 . 5 . 337–56 . May 2014 . 24751816 . 10.1038/nrd4286 . 12172346 .
  10. Baud MG, Lin-Shiao E, Cardote T, Tallant C, Pschibul A, Chan KH, Zengerle M, Garcia JR, Kwan TT, Ferguson FM, Ciulli A . Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes . Science . 346 . 6209 . 638–41 . October 2014 . 25323695 . 4458378 . 10.1126/science.1249830 .
  11. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Chapman TD, Roberts EJ, Soden PE, Auger KR, Mirguet O, Doehner K, Delwel R, Burnett AK, Jeffrey P, Drewes G, Lee K, Huntly BJ, Kouzarides T . Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia . Nature . 478 . 7370 . 529–33 . October 2011 . 21964340 . 3679520 . 10.1038/nature10509 . 2011Natur.478..529D .
  12. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, Vakoc CR . RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia . Nature . 478 . 7370 . 524–8 . August 2011 . 21814200 . 3328300 . 10.1038/nature10334 . 2011Natur.478..524Z .
  13. Da Costa D, Agathanggelou A, Perry T, Weston V, Petermann E, Zlatanou A, Oldreive C, Wei W, Stewart G, Longman J, Smith E, Kearns P, Knapp S, Stankovic T . BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia . en . Blood Cancer Journal . 3 . 7 . e126 . July 2013 . 23872705 . 3730202 . 10.1038/bcj.2013.24 .
  14. Web site: Jay Bradner: Open-source cancer research | Talk Video . 27 October 2011 . TED.com . 2015-04-12.
  15. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, Sims RJ . Targeting MYC dependence in cancer by inhibiting BET bromodomains . Proceedings of the National Academy of Sciences of the United States of America . 108 . 40 . 16669–74 . October 2011 . 21949397 . 3189078 . 10.1073/pnas.1108190108 . 2011PNAS..10816669M . free .
  16. Alderton GK . Targeting MYC? You BET . Nature Reviews. Drug Discovery . 10 . 10 . 732–3 . September 2011 . 21959283 . 10.1038/nrd3569 . 39567104 .
  17. Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA . Functions of BET proteins in erythroid gene expression . Blood . 125 . 18 . 2825–34 . April 2015 . 25696920 . 10.1182/blood-2014-10-607309 . 4424630.
  18. Korkut A, Wang W, Demir E, Aksoy BA, Jing X, Molinelli EJ, Babur Ö, Bemis DL, Onur Sumer S, Solit DB, Pratilas CA, Sander C . Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells . eLife . 4 . August 2015 . 26284497 . 4539601 . 10.7554/elife.04640 . free .
  19. Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ, Gillespie SM, Fernandez D, Ku M, Wang H, Piccioni F, Silver SJ, Jain M, Pearson D, Kluk MJ, Ott CJ, Shultz LD, Brehm MA, Greiner DL, Gutierrez A, Stegmaier K, Kung AL, Root DE, Bradner JE, Aster JC, Kelliher MA, Bernstein BE . An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia . Nature Genetics . 46 . 4 . 364–70 . April 2014 . 24584072 . 4086945 . 10.1038/ng.2913 .
  20. Web site: 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 . 2015-04-12.
  21. Web site: Site . Oncoethix . 2015-04-12.
  22. Web site: Stellar Science, Breakthrough Medicine – Constellation Pharmaceuticals . Constellationpharma.com . 2015-04-12.
  23. Web site: Home - Resverlogix Corp . Resverlogix.com . 2015-05-05.
  24. Web site: Developing Best in Class BET Inhibitors for Oncology & AI: from Discovery to the Clinic . Kevin G. . McLure . vanc . EpiCongress . July 2014 .
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  26. https://clinicaltrials.gov/ct2/results?term=GSK525762&Search=Search GSK525762 clinical studies
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  28. Web site: Small molecule selective bromodomain inhibitors for treating cancer and other diseases . Tensha Therapeutics . 2015-04-12.
  29. Moros A, Rodríguez V, Saborit-Villarroya I, Montraveta A, Balsas P, Sandy P, Martínez A, Wiestner A, Normant E, Campo E, Pérez-Galán P, Colomer D, Roué G . Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma . Leukemia . 28 . 10 . 2049–59 . October 2014 . 24721791 . 10.1038/leu.2014.106 . 205195668 . https://web.archive.org/web/20150418203921/http://www.constellationpharma.com/2014/12/synergistic-antitumor-activity-of-lenalidomide-with-the-bet-bromodomain-inhibitor-cpi203-in-bortezomib-resistant-mantle-cell-lymphoma/ . 18 April 2015 .
  30. Web site: Search of: bet inhibitor - List Results - ClinicalTrials.gov. ClinicalTrials.gov. 1 June 2015.
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