BET inhibitor

"BET inhibitors" are a class of drugs with anti-cancer, immunosuppressive, and other effects in clinical trials in the United States and Europe and widely used in research. These molecules 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]

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[3]), Oncoethix,[4] Constellation pharmaceuticals,[5] Resverlogix Corp[6] and Zenith epigenetics.[7] Notable BET inhibitors include:

JQ1 - commonly used in research studies and distributed free of charge by the James Bradner laboratory at the Dana Farber Cancer Institute [8]

I-BET 151 (GSK1210151A) - widely used in research applications[9]

I-BET 762 (GSK525762) - in clinical trials evaluating safety and efficacy in patients with NUT midline carcinoma and hematologic malignancies

OTX-015 - phase I trials results in patients with hematologic malignancies are available.[10] Clinical trial testing conditions in patients with hematologic malignancies, solid tumors, glioblastoma multiforme, and NUT midline carcinoma

TEN-010 - created by Tensha therapeutics[11]

CPI-203 - shown to be effective in multiple myeloma when given in combination with lenalidomide.[12]

CPI-0610 - currently being evaluated in phase I clinical trials for lymphoma, multiple myeloma, and other hematologic cancers.[13]

RVX-208 - created by Resverlogix Corp.[14] and being evaluated in clinical trials for treatment of atherosclerosis and associated cardiovascular disease.[15]

Preclinical studies have also described compounds that act both as BET inhibitors and as inhibitors of specific kinases.[16] These include:

LY294002[17]

Mechanism of action in cancer

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 [18][19] and multiple myeloma 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.[20][21][22] BRD2 and BRD3 are functionally redundant and may be more important as therapeutic targets than is appreciated in studies depleting each BET protein individually.[23]

Use in other applications

BET inhibitors have been shown to limit the development of heart failure in mouse models.[24][25]

The use of BET inhibitors has been proposed as a method of male birth control due to their ability to inhibit the testis-specific BET protein BRDT.[26][27]

See also

References

  1. ↑ Garnier, J. M.; Sharp, P. P.; Burns, C. J. (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, C. R. (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. ↑ "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.
  4. ↑ "Site". Oncoethix. Retrieved 2015-04-12.
  5. ↑ "Stellar Science, Breakthrough Medicine - Constellation Pharmaceuticals". Constellationpharma.com. Retrieved 2015-04-12.
  6. ↑ http://www.resverlogix.com/
  7. ↑ http://www.zenithepigenetics.com/upload/media_element/16/01/zenith-epigenetics-presentation---epicongress-boston-july-2014.pdf
  8. ↑ "Bradner Lab - Probes". Bradner.dfci.harvard.edu. Retrieved 2015-04-12.
  9. ↑ Di Costanzo, A; Del Gaudio, N; Migliaccio, A; Altucci, L (2014). "Epigenetic drugs against cancer: An evolving landscape". Archives of Toxicology 88 (9): 1651–68. doi:10.1007/s00204-014-1315-6. PMID 25085708.
  10. ↑ 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. PMID 25795799.
  11. ↑ "Small molecule selective bromodomain inhibitors for treating cancer and other diseases". Tensha Therapeutics. Retrieved 2015-04-12.
  12. ↑ http://www.constellationpharma.com/2014/12/synergistic-antitumor-activity-of-lenalidomide-with-the-bet- bromodomain-inhibitor-cpi203-in-bortezomib-resistant-mantle-cell-lymphoma/
  13. ↑ https://www.clinicaltrials.gov/ct2/results?term=bet+inhibitor&Search=Search
  14. ↑ http://www.resverlogix.com/
  15. ↑ J. Johansson, A. Gordon, C. Halliday, N.C. Wong, Effects of RVX-208 on major adverse cardiac events (MACE), apolipoprotein A-I and High-Density-Lipoproteins; A post-hoc analysis from the pooled SUSTAIN and ASSURE clinical trials, Eur Heart J Suppl, 35 (2014) 732-724.
  16. ↑ PMID 24584101 (PubMed)
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  17. ↑ PMID 24533473 (PubMed)
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  18. ↑ Dawson, M. A.; Prinjha, R. K.; Dittmann, A; Giotopoulos, G; Bantscheff, M; Chan, W. I.; Robson, S. C.; Chung, C. W.; Hopf, C; Savitski, M. M.; Huthmacher, C; Gudgin, E; Lugo, D; Beinke, S; Chapman, T. D.; Roberts, E. J.; Soden, P. E.; Auger, K. R.; Mirguet, O; Doehner, K; Delwel, R; Burnett, A. K.; Jeffrey, P; Drewes, G; Lee, K; Huntly, B. J.; Kouzarides, T (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.
  19. ↑ Zuber, J.; Shi, J.; Wang, E.; Rappaport, A. R.; Herrmann, H.; Sison, E. A.; Magoon, D.; Qi, J.; Blatt, K.; Wunderlich, M.; Taylor, M. J.; Johns, C.; Chicas, A.; Mulloy, J. C.; Kogan, S. C.; Brown, P.; Valent, P.; Bradner, J. E.; Lowe, S. W.; Vakoc, C. R. (2011). "RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia". Nature 478 (7370): 524–528. doi:10.1038/nature10334. PMC 3328300. PMID 21814200.
  20. ↑ "Jay Bradner: Open-source cancer research | Talk Video". TED.com. Retrieved 2015-04-12.
  21. ↑ Mertz, J. A.; Conery, A. R.; Bryant, B. M.; Sandy, P; Balasubramanian, S; Mele, D. A.; Bergeron, L; Sims Rj, 3rd (2011). "Targeting MYC dependence in cancer by inhibiting BET bromodomains". Proceedings of the National Academy of Sciences 108 (40): 16669–74. doi:10.1073/pnas.1108190108. PMC 3189078. PMID 21949397.
  22. ↑ Alderton, G. K. (2011). "Targeting MYC? You BET". Nature Reviews Drug Discovery 10 (10): 732–3. doi:10.1038/nrd3569. PMID 21959283.
  23. ↑ Stonestrom, A. J.; Hsu, S. C.; Jahn, K. S.; Huang, P; Keller, C. A.; Giardine, B. M.; Kadauke, S; Campbell, A. E.; Evans, P; Hardison, R. C.; Blobel, G. A. (2015). "Functions of BET proteins in erythroid gene expression". Blood. doi:10.1182/blood-2014-10-607309. PMID 25696920.
  24. ↑ 10:09 am (2013-08-02). "New Target in Heart Failure | HMS". Hms.harvard.edu. Retrieved 2015-04-12.
  25. ↑ "New Designer Compound Treats Heart Failure by Targeting Cell Nucleus | Case Western Reserve University School of Medicine". Casemed.case.edu. 2013-08-01. Retrieved 2015-04-12.
  26. ↑ Matzuk, M. M.; McKeown, M. R.; Filippakopoulos, P.; Li, Q.; Ma, L.; Agno, J. E.; Lemieux, M. E.; Picaud, S.; Yu, R. N.; Qi, J.; Knapp, S.; Bradner, J. E. (2012). "Small-Molecule Inhibition of BRDT for Male Contraception". Cell 150 (4): 673–684. doi:10.1016/j.cell.2012.06.045. PMC 3420011. PMID 22901802.
  27. ↑ "Male Birth Control Possible? JQ1 Compound Decreases Mice's Sperm Count, Quality". Huffingtonpost.com. 2012-08-16. Retrieved 2015-04-12.