请输入您要查询的百科知识：

　

词条 BET inhibitor
释义

  1. Discovery and development

  2. Mechanism of action

  3. Specific BET inhibitors

      Targeting both BD1 and BD2 (bromodomains)    Selective targeting of BD1    Selective targeting of BD2    Dual kinase-bromodomain inhibitors    Bivalent BET inhibitors  

  4. See also

  5. References

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 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

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

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)

  • I-BET 151 (GSK1210151A)[24]
  • I-BET 762 (GSK525762)[25]
  • OTX-015[26]
  • TEN-010[27]
  • CPI-203[28]
  • CPI-0610[29]

Selective targeting of BD1

  • olinone, e.g. to affect the differentiation of oligodendrocyte progenitor cells.[30]{{rp|4.1}}[31]

Selective targeting of BD2

  • RVX-208[32]

Dual kinase-bromodomain inhibitors

  • LY294002 (some PI3K and BRD2, BRD3, and BRD4)[33][34]

Bivalent BET inhibitors

  • AZD5153[35][36][37]
  • MT-1[38]
  • MS645[39]

See also

{{div col|colwidth=22em}}
  • Bromodomain
  • Bromodomain-containing protein
  • NUT midline carcinoma
  • BRD2
  • BRD3
  • BRD4
  • BRDT
{{div col end}}

References

1. ^{{cite journal | vauthors = Garnier JM, Sharp PP, Burns CJ | title = BET bromodomain inhibitors: a patent review | journal = Expert Opinion on Therapeutic Patents | volume = 24 | issue = 2 | pages = 185–99 | date = February 2014 | pmid = 24261714 | doi = 10.1517/13543776.2014.859244 }}
2. ^{{cite journal | vauthors = Shi J, Vakoc CR | title = The mechanisms behind the therapeutic activity of BET bromodomain inhibition | journal = Molecular Cell | volume = 54 | issue = 5 | pages = 728–36 | date = June 2014 | pmid = 24905006 | pmc = 4236231 | doi = 10.1016/j.molcel.2014.05.016 }}
3. ^{{cite patent |country=JP |number=2008156311}}
4. ^{{cite patent |country=JP |number=H0228181}}
5. ^{{cite journal | vauthors = 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 | title = Selective inhibition of BET bromodomains | journal = Nature | volume = 468 | issue = 7327 | pages = 1067–73 | date = December 2010 | pmid = 20871596 | pmc = 3010259 | doi = 10.1038/nature09504 }}
6. ^{{cite journal | vauthors = 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 | title = Suppression of inflammation by a synthetic histone mimic | journal = Nature | volume = 468 | issue = 7327 | pages = 1119–23 | date = December 2010 | pmid = 21068722 | doi = 10.1038/nature09589 }}
7. ^{{cite journal | vauthors = 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 | title = PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains | journal = Cancer Research | volume = 73 | issue = 11 | pages = 3336–46 | date = June 2013 | pmid = 23576556 | pmc = 3673830 | doi = 10.1158/0008-5472.CAN-12-3292 }}
8. ^{{cite journal | vauthors = Filippakopoulos P, Knapp S | title = Targeting bromodomains: epigenetic readers of lysine acetylation | journal = Nature Reviews. Drug Discovery | volume = 13 | issue = 5 | pages = 337–56 | date = May 2014 | pmid = 24751816 | doi = 10.1038/nrd4286 }}
9. ^{{cite journal | vauthors = Baud MG, Lin-Shiao E, Cardote T, Tallant C, Pschibul A, Chan KH, Zengerle M, Garcia JR, Kwan TT, Ferguson FM, Ciulli A | title = Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes | journal = Science | volume = 346 | issue = 6209 | pages = 638–41 | date = October 2014 | pmid = 25323695 | pmc = 4458378 | doi = 10.1126/science.1249830 }}
10. ^{{cite journal | vauthors = 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 | title = Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia | journal = Nature | volume = 478 | issue = 7370 | pages = 529–33 | date = October 2011 | pmid = 21964340 | pmc = 3679520 | doi = 10.1038/nature10509 }}
11. ^{{cite journal | vauthors = 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 | title = RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia | journal = Nature | volume = 478 | issue = 7370 | pages = 524–8 | date = August 2011 | pmid = 21814200 | pmc = 3328300 | doi = 10.1038/nature10334 }}
12. ^{{cite journal | vauthors = 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 | title = BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia | language = en | journal = Blood Cancer Journal | volume = 3 | issue = 7 | pages = e126 | date = July 2013 | pmid = 23872705 | pmc = 3730202 | doi = 10.1038/bcj.2013.24 }}
13. ^{{cite web|url=http://www.ted.com/talks/jay_bradner_open_source_cancer_research?language=en |title=Jay Bradner: Open-source cancer research | Talk Video |publisher=TED.com |date= |accessdate=2015-04-12}}
14. ^{{cite journal | vauthors = Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, Sims RJ | title = Targeting MYC dependence in cancer by inhibiting BET bromodomains | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 40 | pages = 16669–74 | date = October 2011 | pmid = 21949397 | pmc = 3189078 | doi = 10.1073/pnas.1108190108 }}
15. ^{{cite journal | vauthors = Alderton GK | title = Targeting MYC? You BET | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 10 | pages = 732–3 | date = September 2011 | pmid = 21959283 | doi = 10.1038/nrd3569 }}
16. ^{{cite journal | vauthors = Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA | title = Functions of BET proteins in erythroid gene expression | journal = Blood | volume = 125 | issue = 18 | pages = 2825–34 | date = April 2015 | pmid = 25696920 | doi = 10.1182/blood-2014-10-607309 | pmc=4424630}}
17. ^{{cite journal | vauthors = 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 | title = Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells | journal = eLife | volume = 4 | date = August 2015 | pmid = 26284497 | pmc = 4539601 | doi = 10.7554/elife.04640 }}
18. ^{{cite journal | vauthors = 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 | title = An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia | journal = Nature Genetics | volume = 46 | issue = 4 | pages = 364–70 | date = April 2014 | pmid = 24584072 | pmc = 4086945 | doi = 10.1038/ng.2913 }}
19. ^{{cite web|url=http://www.mercknewsroom.com/news-release/corporate-news/merck-acquires-oncoethix-privately-held-oncology-company-developing-nove |title=Merck Acquires OncoEthix, a Privately Held Oncology Company Developing Novel BET Inhibitors for Hematological and Solid Cancers | Merck Newsroom Home |publisher=Mercknewsroom.com |date=2014-12-18 |accessdate=2015-04-12}}
20. ^{{cite web|url=http://www.oncoethix.com/ |title=Site |publisher=Oncoethix |date= |accessdate=2015-04-12}}
21. ^{{cite web|url=http://www.constellationpharma.com/ |title=Stellar Science, Breakthrough Medicine – Constellation Pharmaceuticals |publisher=Constellationpharma.com |date= |accessdate=2015-04-12}}
22. ^{{cite web|url=http://www.resverlogix.com/ |title=Home - Resverlogix Corp |publisher=Resverlogix.com |date= |accessdate=2015-05-05}}
23. ^{{cite web | url = http://www.zenithepigenetics.com/upload/media_element/16/01/zenith-epigenetics-presentation---epicongress-boston-july-2014.pdf | title = Developing Best in Class BET Inhibitors for Oncology & AI: from Discovery to the Clinic | publisher = | first = Kevin G. | last = McLure | name-list-format = vanc | work = EpiCongress | date = July 2014 }}
24. ^{{cite journal | vauthors = Di Costanzo A, Del Gaudio N, Migliaccio A, Altucci L | title = Epigenetic drugs against cancer: an evolving landscape | journal = Archives of Toxicology | volume = 88 | issue = 9 | pages = 1651–68 | date = September 2014 | pmid = 25085708 | doi = 10.1007/s00204-014-1315-6 }}
25. ^[https://clinicaltrials.gov/ct2/results?term=GSK525762&Search=Search GSK525762 clinical studies]
26. ^{{Cite journal | year = 2015 | author1 = Herait | first1 = P | title = O7.3BET-bromodomain (BRD) inhibitor OTX015: Final results of the dose-finding part of a phase I study in hematologic malignancies | journal = Annals of Oncology | volume = 26 Suppl 2 | pages = ii10 | last2 = Dombret | first2 = H | last3 = Thieblemont | first3 = C | last4 = Facon | first4 = T | last5 = Stathis | first5 = A | last6 = Cunningham | first6 = D | last7 = Palumbo | first7 = A | last8 = Vey | first8 = N | last9 = Michallet | first9 = M | last10 = Recher | first10 = C | last11 = Rezai | first11 = K | last12 = Preudhomme | first12 = C | name-list-format = vanc | doi = 10.1093/annonc/mdv085.3 }}
27. ^{{cite web|url=http://www.tenshatherapeutics.com/ |title=Small molecule selective bromodomain inhibitors for treating cancer and other diseases |publisher=Tensha Therapeutics |date= |accessdate=2015-04-12}}
28. ^{{cite journal | vauthors = 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 | title = Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma | journal = Leukemia | volume = 28 | issue = 10 | pages = 2049–59 | date = October 2014 | pmid = 24721791 | doi = 10.1038/leu.2014.106 | url = http://www.constellationpharma.com/2014/12/synergistic-antitumor-activity-of-lenalidomide-with-the-bet-bromodomain-inhibitor-cpi203-in-bortezomib-resistant-mantle-cell-lymphoma/ | archiveurl = 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/ | archivedate = 18 April 2015 }}
29. ^{{cite web|title=Search of: bet inhibitor - List Results - ClinicalTrials.gov|url=https://www.clinicaltrials.gov/ct2/results?term=bet+inhibitor&Search=Search|website=ClinicalTrials.gov|accessdate=1 June 2015}}
30. ^{{cite journal | vauthors = Ntranos A, Casaccia P | title = Bromodomains: Translating the words of lysine acetylation into myelin injury and repair | journal = Neuroscience Letters | volume = 625 | pages = 4–10 | date = June 2016 | pmid = 26472704 | pmc = 4841751 | doi = 10.1016/j.neulet.2015.10.015 | url = https://www.researchgate.net/publication/282912027_Bromodomains_Translating_the_words_of_lysine_acetylation_into_myelin_injury_and_repair }}
31. ^{{cite journal | vauthors = 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 | title = Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression | journal = Chemistry & Biology | volume = 21 | issue = 7 | pages = 841–854 | date = July 2014 | pmid = 24954007 | pmc = 4104156 | doi = 10.1016/j.chembiol.2014.05.009 }}
32. ^{{cite journal | vauthors = 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 | title = RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 49 | pages = 19754–9 | date = December 2013 | pmid = 24248379 | pmc = 3856850 | doi = 10.1073/pnas.1310658110 }}
33. ^{{cite journal | vauthors = 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 | title = The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains | journal = ACS Chemical Biology | volume = 9 | issue = 2 | pages = 495–502 | date = February 2014 | pmid = 24533473 | doi = 10.1021/cb400789e }}
34. ^{{cite journal | vauthors = 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 | title = Dual kinase-bromodomain inhibitors for rationally designed polypharmacology | journal = Nature Chemical Biology | volume = 10 | issue = 4 | pages = 305–12 | date = April 2014 | pmid = 24584101 | pmc = 3998711 | doi = 10.1038/nchembio.1471 }}
35. ^{{cite journal | vauthors = 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 | title = 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 = Journal of Medicinal Chemistry | volume = 59 | issue = 17 | pages = 7801–17 | date = September 2016 | pmid = 27528113 | doi = 10.1021/acs.jmedchem.6b00070 }}
36. ^{{cite journal | vauthors = 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 | title = AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies | journal = Molecular Cancer Therapeutics | volume = 15 | issue = 11 | pages = 2563–2574 | date = November 2016 | pmid = 27573426 | doi = 10.1158/1535-7163.MCT-16-0141 }}
37. ^{{cite journal | vauthors = 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 | title = Potent and selective bivalent inhibitors of BET bromodomains | journal = Nature Chemical Biology | volume = 12 | issue = 12 | pages = 1097–1104 | date = December 2016 | pmid = 27775716 | doi = 10.1038/nchembio.2210 }}
38. ^{{cite journal | vauthors = Tanaka M, Roberts JM, Seo HS, Souza A, Paulk J, Scott TG, DeAngelo SL, Dhe-Paganon S, Bradner JE | title = Design and characterization of bivalent BET inhibitors | journal = Nature Chemical Biology | volume = 12 | issue = 12 | pages = 1089–1096 | date = December 2016 | pmid = 27775715 | pmc = 5117811 | doi = 10.1038/nchembio.2209 }}
39. ^{{cite journal | vauthors = 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 | title = Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 31 | pages = 7949–7954 | date = July 2018 | pmid = 30012592 | pmc = 6077712 | doi = 10.1073/pnas.1720000115 }}

1 : Drugs blocking protein-protein interactions
随便看

　

开放百科全书收录14589846条英语、德语、日语等多语种百科知识，基本涵盖了大多数领域的百科知识，是一部内容自由、开放的电子版国际百科全书。

　

Copyright © 2023 OENC.NET All Rights Reserved
京ICP备2021023879号 更新时间：2024/9/25 2:26:07