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BET inhibitor

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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

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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

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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

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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)

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Selective targeting of BD1

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Selective targeting of BD2

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Dual kinase-bromodomain inhibitors

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Bivalent BET inhibitors

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See also

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References

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  1. ^ Garnier JM, Sharp PP, Burns CJ (February 2014). "BET bromodomain inhibitors: a patent review". Expert Opinion on Therapeutic Patents. 24 (2): 185–99. doi:10.1517/13543776.2014.859244. PMID 24261714. S2CID 24647727.
  2. ^ Shi J, Vakoc CR (June 2014). "The mechanisms behind the therapeutic activity of BET bromodomain inhibition". Molecular Cell. 54 (5): 728–36. doi:10.1016/j.molcel.2014.05.016. PMC 4236231. PMID 24905006.
  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. 
  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 (December 2010). "Suppression of inflammation by a synthetic histone mimic". Nature. 468 (7327): 1119–23. Bibcode:2010Natur.468.1119N. doi:10.1038/nature09589. PMC 5415086. PMID 21068722.
  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 (December 2013). "RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist". PLOS ONE. 8 (12): e83190. doi:10.1371/journal.pone.0083190. PMC 3877016. PMID 24391744.
  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 (December 2010). "Selective inhibition of BET bromodomains". Nature. 468 (7327): 1067–73. Bibcode:2010Natur.468.1067F. doi:10.1038/nature09504. PMC 3010259. PMID 20871596.
  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 (June 2013). "PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains". Cancer Research. 73 (11): 3336–46. doi:10.1158/0008-5472.CAN-12-3292. PMC 3673830. PMID 23576556.
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  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 (October 2011). "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia". Nature. 478 (7370): 529–33. Bibcode:2011Natur.478..529D. doi:10.1038/nature10509. PMC 3679520. PMID 21964340.
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  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 (July 2013). "BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia". Blood Cancer Journal. 3 (7): e126. doi:10.1038/bcj.2013.24. PMC 3730202. PMID 23872705.
  14. ^ "Jay Bradner: Open-source cancer research | Talk Video". TED.com. 27 October 2011. Retrieved 2015-04-12.
  15. ^ Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, Sims RJ (October 2011). "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. Bibcode:2011PNAS..10816669M. doi:10.1073/pnas.1108190108. PMC 3189078. PMID 21949397.
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  17. ^ Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA (April 2015). "Functions of BET proteins in erythroid gene expression". Blood. 125 (18): 2825–34. doi:10.1182/blood-2014-10-607309. PMC 4424630. PMID 25696920.
  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 (August 2015). "Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells". eLife. 4. doi:10.7554/elife.04640. PMC 4539601. PMID 26284497.
  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 (April 2014). "An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia". Nature Genetics. 46 (4): 364–70. doi:10.1038/ng.2913. PMC 4086945. PMID 24584072.
  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.
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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.
  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 (October 2014). "Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma". Leukemia. 28 (10): 2049–59. doi:10.1038/leu.2014.106. PMID 24721791. S2CID 205195668. Archived from the original on 18 April 2015.
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  33. ^ Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, Diez-Dacal B, Philpott M, Bountra C, Lingard H, Fedorov O, Müller S, Brennan PE, Knapp S, Filippakopoulos P (December 2013). "RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain". Proceedings of the National Academy of Sciences of the United States of America. 110 (49): 19754–9. Bibcode:2013PNAS..11019754P. doi:10.1073/pnas.1310658110. PMC 3856850. PMID 24248379.
  34. ^ Faivre EJ, McDaniel KF, Albert DH, Mantena SR, Plotnik JP, Wilcox D, Zhang L, Bui MH, Sheppard GS, Wang L, Sehgal V, Lin X, Huang X, Lu X, Uziel T, Hessler P, Lam LT, Bellin RJ, Mehta G, Fidanze S, Pratt JK, Liu D, Hasvold LA, Sun C, Panchal SC, Nicolette JJ, Fossey SL, Park CH, Longenecker K, Bigelow L, Torrent M, Rosenberg SH, Kati WM, Shen Y (February 2020). "Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer". Nature. 578 (7794): 306–310. Bibcode:2020Natur.578..306F. doi:10.1038/s41586-020-1930-8. PMID 31969702. S2CID 210866404.
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  36. ^ Ciceri P, Müller S, O'Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, Lasater EA, Pallares G, Picaud S, Wells C, Martin S, Wodicka LM, Shah NP, Treiber DK, Knapp S (April 2014). "Dual kinase-bromodomain inhibitors for rationally designed polypharmacology". Nature Chemical Biology. 10 (4): 305–12. doi:10.1038/nchembio.1471. PMC 3998711. PMID 24584101.
  37. ^ Bradbury RH, Callis R, Carr GR, Chen H, Clark E, Feron L, Glossop S, Graham MA, Hattersley M, Jones C, Lamont SG, Ouvry G, Patel A, Patel J, Rabow AA, Roberts CA, Stokes S, Stratton N, Walker GE, Ward L, Whalley D, Whittaker D, Wrigley G, Waring MJ (September 2016). "Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153)". Journal of Medicinal Chemistry. 59 (17): 7801–17. doi:10.1021/acs.jmedchem.6b00070. PMID 27528113.
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