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[edit]

Thienodiazepine BET inhibitors were discovered 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] However, these molecules remained largely unknown until 2010 when both the use of JQ1 in NUT midline carcinoma[5] and of I-BET 762 in sepsis were published.[6] Since this time a number of molecules have been described that are capable of targeting BET bromodomains.[7]

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).[8] 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.[9]

Mechanism of action[edit]

Interest in using BET inhibitors in cancer began with the observation that chromosomal translocations involving BET genes BRD3 and BRD4 drove the pathogenesis the rare cancer NUT midline carcinoma. Subsequent research uncovered the dependence of some forms of acute myeloid leukemia,[10][11] multiple myeloma and acute lymphoblastic leukemia[12] 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.[13][14][15] BRD2 and BRD3 are functionally redundant and may be more important as therapeutic targets than is appreciated in studies depleting each BET protein individually.[16] 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 RAF-inhibitor (vemurafenib) for RAF-inhibitor resistant melanomas carrying the BRAFV600E mutation.[17][18]

Specific BET inhibitors[edit]

BET inhibitors have been developed by publicly funded research labs as well as pharmaceutical companies including GlaxoSmithKline, Oncoethix (purchased by Merck & Co. in 2014[19]), Oncoethix,[20] Constellation pharmaceuticals,[21] Resverlogix Corp[22] and Zenith epigenetics.[23] Notable BET inhibitors include:

Targeting both BD1 and BD2 (bromodomains)[edit]

Selective targeting of BD1[edit]

Selective targeting of BD2[edit]

Dual kinase-bromodomain inhibitors[edit]

Bivalent BET inhibitors[edit]

See also[edit]


  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.
  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 2008156311 
  4. ^ JP H0228181 
  5. ^ 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. doi:10.1038/nature09504. PMC 3010259. PMID 20871596.
  6. ^ 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. doi:10.1038/nature09589. PMID 21068722.
  7. ^ 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.
  8. ^ Filippakopoulos P, Knapp S (May 2014). "Targeting bromodomains: epigenetic readers of lysine acetylation". Nature Reviews. Drug Discovery. 13 (5): 337–56. doi:10.1038/nrd4286. PMID 24751816.
  9. ^ Baud MG, Lin-Shiao E, Cardote T, Tallant C, Pschibul A, Chan KH, Zengerle M, Garcia JR, Kwan TT, Ferguson FM, Ciulli A (October 2014). "Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes". Science. 346 (6209): 638–41. doi:10.1126/science.1249830. PMC 4458378. PMID 25323695.
  10. ^ 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. doi:10.1038/nature10509. PMC 3679520. PMID 21964340.
  11. ^ 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 (August 2011). "RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia". Nature. 478 (7370): 524–8. doi:10.1038/nature10334. PMC 3328300. PMID 21814200.
  12. ^ 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.
  13. ^ "Jay Bradner: Open-source cancer research | Talk Video". Retrieved 2015-04-12.
  14. ^ 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. doi:10.1073/pnas.1108190108. PMC 3189078. PMID 21949397.
  15. ^ Alderton GK (September 2011). "Targeting MYC? You BET". Nature Reviews. Drug Discovery. 10 (10): 732–3. doi:10.1038/nrd3569. PMID 21959283.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ "Merck Acquires OncoEthix, a Privately Held Oncology Company Developing Novel BET Inhibitors for Hematological and Solid Cancers | Merck Newsroom Home". 2014-12-18. Retrieved 2015-04-12.
  20. ^ "Site". Oncoethix. Retrieved 2015-04-12.
  21. ^ "Stellar Science, Breakthrough Medicine – Constellation Pharmaceuticals". Retrieved 2015-04-12.
  22. ^ "Home - Resverlogix Corp". Retrieved 2015-05-05.
  23. ^ McLure KG (July 2014). "Developing Best in Class BET Inhibitors for Oncology & AI: from Discovery to the Clinic" (PDF). EpiCongress.
  24. ^ "Bradner Lab – Probes". Retrieved 2015-04-12.
  25. ^ Di Costanzo A, Del Gaudio N, Migliaccio A, Altucci L (September 2014). "Epigenetic drugs against cancer: an evolving landscape". Archives of Toxicology. 88 (9): 1651–68. doi:10.1007/s00204-014-1315-6. PMID 25085708.
  26. ^ GSK525762 clinical studies
  27. ^ Herait P, Dombret H, Thieblemont C, Facon T, Stathis A, Cunningham D, Palumbo A, Vey N, Michallet M, Recher C, Rezai K, Preudhomme C (2015). "O7.3BET-bromodomain (BRD) inhibitor OTX015: Final results of the dose-finding part of a phase I study in hematologic malignancies". Annals of Oncology. 26 Suppl 2: ii10. doi:10.1093/annonc/mdv085.3.
  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. Archived from the original on 18 April 2015.
  30. ^ "Search of: bet inhibitor - List Results -". Retrieved 1 June 2015.
  31. ^ Ntranos A, Casaccia P (June 2016). "Bromodomains: Translating the words of lysine acetylation into myelin injury and repair". Neuroscience Letters. 625: 4–10. doi:10.1016/j.neulet.2015.10.015. PMC 4841751. PMID 26472704.
  32. ^ Gacias M, Gerona-Navarro G, Plotnikov AN, Zhang G, Zeng L, Kaur J, Moy G, Rusinova E, Rodriguez Y, Matikainen B, Vincek A, Joshua J, Casaccia P, Zhou MM (July 2014). "Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression". Chemistry & Biology. 21 (7): 841–854. doi:10.1016/j.chembiol.2014.05.009. PMC 4104156. PMID 24954007.
  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. doi:10.1073/pnas.1310658110. PMC 3856850. PMID 24248379.
  34. ^ Dittmann A, Werner T, Chung CW, Savitski MM, Fälth Savitski M, Grandi P, Hopf C, Lindon M, Neubauer G, Prinjha RK, Bantscheff M, Drewes G (February 2014). "The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains". ACS Chemical Biology. 9 (2): 495–502. doi:10.1021/cb400789e. PMID 24533473.
  35. ^ 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.
  36. ^ 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.
  37. ^ Rhyasen GW, Hattersley MM, Yao Y, Dulak A, Wang W, Petteruti P, Dale IL, Boiko S, Cheung T, Zhang J, Wen S, Castriotta L, Lawson D, Collins M, Bao L, Ahdesmaki MJ, Walker G, O'Connor G, Yeh TC, Rabow AA, Dry JR, Reimer C, Lyne P, Mills GB, Fawell SE, Waring MJ, Zinda M, Clark E, Chen H (November 2016). "AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies". Molecular Cancer Therapeutics. 15 (11): 2563–2574. doi:10.1158/1535-7163.MCT-16-0141. PMID 27573426.
  38. ^ Waring MJ, Chen H, Rabow AA, Walker G, Bobby R, Boiko S, Bradbury RH, Callis R, Clark E, Dale I, Daniels DL, Dulak A, Flavell L, Holdgate G, Jowitt TA, Kikhney A, McAlister M, Méndez J, Ogg D, Patel J, Petteruti P, Robb GR, Robers MB, Saif S, Stratton N, Svergun DI, Wang W, Whittaker D, Wilson DM, Yao Y (December 2016). "Potent and selective bivalent inhibitors of BET bromodomains". Nature Chemical Biology. 12 (12): 1097–1104. doi:10.1038/nchembio.2210. PMID 27775716.
  39. ^ Tanaka M, Roberts JM, Seo HS, Souza A, Paulk J, Scott TG, DeAngelo SL, Dhe-Paganon S, Bradner JE (December 2016). "Design and characterization of bivalent BET inhibitors". Nature Chemical Biology. 12 (12): 1089–1096. doi:10.1038/nchembio.2209. PMC 5117811. PMID 27775715.
  40. ^ Ren C, Zhang G, Han F, Fu S, Cao Y, Zhang F, Zhang Q, Meslamani J, Xu Y, Ji D, Cao L, Zhou Q, Cheung KL, Sharma R, Babault N, Yi Z, Zhang W, Walsh MJ, Zeng L, Zhou MM (July 2018). "Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth". Proceedings of the National Academy of Sciences of the United States of America. 115 (31): 7949–7954. doi:10.1073/pnas.1720000115. PMC 6077712. PMID 30012592.