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]

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 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[10][11] 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.[12][13][14] BRD2 and BRD3 are functionally redundant and may be more important as therapeutic targets than is appreciated in studies depleting each BET protein individually.[15] 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. [16][17]


Use in other applications

BET inhibition prevents death in mouse models of sepsis, attenuates autoimmunity, and lessens damage from overactive inflammatory responses in the lung.[18][19][20]

Pre-clinical studies have also demonstrated efficacy in applications that would require chronic administration (see below: heart failure and male contraception). As early studies in humans have already demonstrated significant toxicity in the form of thrombocytopenia, and these drugs are likely to have major immunomodulatory effects, it is unclear what the range of safe feasible applications for these molecules will be.

BET inhibitors have been shown to limit the development of heart failure in mouse models.[21][22]

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.[23][24]

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[25]), Oncoethix,[26] Constellation pharmaceuticals,[27] Resverlogix Corp[28] and Zenith epigenetics.[29] Notable BET inhibitors include:

BET inhibitors targeting both bromodomains (BD1 and BD2):

JQ1 – commonly used in research studies and distributed free of charge by the James Bradner laboratory at the Dana Farber Cancer Institute[30]

I-BET 151 (GSK1210151A) – widely used in research applications[31]

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.[32] Clinical trial testing conditions in patients with hematologic malignancies, solid tumors, glioblastoma multiforme, and NUT midline carcinoma

TEN-010 – created by Tensha therapeutics[33]

CPI-203 – shown to be effective in multiple myeloma when given in combination with lenalidomide.[34]

CPI-0610 – currently being evaluated in phase I clinical trials for lymphoma, multiple myeloma, and other hematologic cancers.[35]

BET inhibitors selectively targeting the second bromodomain (BD2):

RVX-208 – created by Resverlogix Corp.[36] and being evaluated in clinical trials for treatment of atherosclerosis and associated cardiovascular disease.[37]

BET inhibitors that also act as kinase inhibitors:[38]

LY294002[39]

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 4236231Freely accessible. PMID 24905006.
  3. ↑ JP 2008156311
  4. ↑ JP H0228181
  5. ↑ Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W. B.; Fedorov, O.; Morse, E. M.; Keates, T.; Hickman, T. T.; Felletar, I.; Philpott, M.; Munro, S.; McKeown, M. R.; Wang, Y.; Christie, A. L.; West, N.; Cameron, M. J.; Schwartz, B.; Heightman, T. D.; La Thangue, N.; French, C. A.; Wiest, O.; Kung, A. L.; Knapp, S.; Bradner, J. E. (2010). "Selective inhibition of BET bromodomains". Nature. 468 (7327): 1067–1073. doi:10.1038/nature09504. PMC 3010259Freely accessible. PMID 20871596.
  6. ↑ Nicodeme, E; Jeffrey, K. L.; Schaefer, U; Beinke, S; Dewell, S; Chung, C. W.; Chandwani, R; Marazzi, I; Wilson, P; Coste, H; White, J; Kirilovsky, J; Rice, C. M.; Lora, J. M.; Prinjha, R. K.; Lee, K; Tarakhovsky, A (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, P. V.; Philpott, M; Fedorov, O; Brennan, P; Bunnage, M. E.; Owen, D. R.; Bradner, J. E.; Taniere, P; O'Sullivan, B; Müller, S; Schwaller, J; Stankovic, T; Knapp, S (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 3673830Freely accessible. PMID 23576556.
  8. ↑ Filippakopoulos, P; Knapp, S (2014). "Targeting bromodomains: Epigenetic readers of lysine acetylation". Nature Reviews Drug Discovery. 13 (5): 337–56. doi:10.1038/nrd4286. PMID 24751816.
  9. ↑ Baud M.G., Lin-Shiao E., Cardote T., Tallant C., Pschibul A., Chan K.H., Zengerle M., Garcia J.R., Kwan T.T., Ferguson F.M., Ciulli A. (2014) A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Science. 2014 Oct 31;346(6209):638-41. doi:10.1126/science.1249830 10.1126/science.1249830 PMID 25323695
  10. ↑ 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 3679520Freely accessible. PMID 21964340.
  11. ↑ 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 3328300Freely accessible. PMID 21814200.
  12. ↑ "Jay Bradner: Open-source cancer research | Talk Video". TED.com. Retrieved 2015-04-12.
  13. ↑ 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 3189078Freely accessible. PMID 21949397.
  14. ↑ Alderton, G. K. (2011). "Targeting MYC? You BET". Nature Reviews Drug Discovery. 10 (10): 732–3. doi:10.1038/nrd3569. PMID 21959283.
  15. ↑ 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. 125: 2825–34. doi:10.1182/blood-2014-10-607309. PMID 25696920.
  16. ↑ 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 (18 August 2015). "Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells.". eLife. 4. PMID 26284497.
  17. ↑ 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. PMID 24584072.
  18. ↑ Bandukwala, H. S.; Gagnon, J; Togher, S; Greenbaum, J. A.; Lamperti, E. D.; Parr, N. J.; Molesworth, A. M.; Smithers, N; Lee, K; Witherington, J; Tough, D. F.; Prinjha, R. K.; Peters, B; Rao, A (2012). "Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors". Proceedings of the National Academy of Sciences. 109 (36): 14532–7. doi:10.1073/pnas.1212264109. PMC 3437860Freely accessible. PMID 22912406.
  19. ↑ Mele, D. A.; Salmeron, A; Ghosh, S; Huang, H. R.; Bryant, B. M.; Lora, J. M. (2013). "BET bromodomain inhibition suppresses TH17-mediated pathology". Journal of Experimental Medicine. 210 (11): 2181–90. doi:10.1084/jem.20130376. PMC 3804955Freely accessible. PMID 24101376.
  20. ↑ Nicodeme, E; Jeffrey, K. L.; Schaefer, U; Beinke, S; Dewell, S; Chung, C. W.; Chandwani, R; Marazzi, I; Wilson, P; Coste, H; White, J; Kirilovsky, J; Rice, C. M.; Lora, J. M.; Prinjha, R. K.; Lee, K; Tarakhovsky, A (2010). "Suppression of inflammation by a synthetic histone mimic". Nature. 468 (7327): 1119–23. doi:10.1038/nature09589. PMID 21068722.
  21. ↑ "New Target in Heart Failure | HMS". Hms.harvard.edu. 2013-08-02. Retrieved 2015-04-12.
  22. ↑ "New Designer Compound Treats Heart Failure by Targeting Cell Nucleus | Case Western Reserve University School of Medicine". Casemed.case.edu. 2013-08-01. Archived from the original on 2015-04-17. Retrieved 2015-04-12.
  23. ↑ 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 3420011Freely accessible. PMID 22901802.
  24. ↑ "Male Birth Control Possible? JQ1 Compound Decreases Mice's Sperm Count, Quality". Huffingtonpost.com. 2012-08-16. Retrieved 2015-04-12.
  25. ↑ "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.
  26. ↑ "Site". Oncoethix. Retrieved 2015-04-12.
  27. ↑ "Stellar Science, Breakthrough Medicine – Constellation Pharmaceuticals". Constellationpharma.com. Retrieved 2015-04-12.
  28. ↑ "Home - Resverlogix Corp". Resverlogix.com. Retrieved 2015-05-05.
  29. ↑ http://www.zenithepigenetics.com/upload/media_element/16/01/zenith-epigenetics-presentation---epicongress-boston-july-2014.pdf
  30. ↑ "Bradner Lab – Probes". Bradner.dfci.harvard.edu. Retrieved 2015-04-12.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ "Small molecule selective bromodomain inhibitors for treating cancer and other diseases". Tensha Therapeutics. Retrieved 2015-04-12.
  34. ↑ 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.
  35. ↑ "Search of: bet inhibitor - List Results - ClinicalTrials.gov". ClinicalTrials.gov. Retrieved 1 June 2015.
  36. ↑ "Home - Resverlogix Corp". Resverlogix.com. Retrieved 2015-05-05.
  37. ↑ 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.
  38. ↑ Ciceri, P; Müller, S; O'Mahony, A; Fedorov, O; Filippakopoulos, P; Hunt, J. P.; Lasater, E. A.; Pallares, G; Picaud, S; Wells, C; Martin, S; Wodicka, L. M.; Shah, N. P.; Treiber, D. K.; Knapp, S (2014). "Dual kinase-bromodomain inhibitors for rationally designed polypharmacology". Nature Chemical Biology. 10 (4): 305–12. doi:10.1038/nchembio.1471. PMC 3998711Freely accessible. PMID 24584101.
  39. ↑ Dittmann, A; Werner, T; Chung, C. W.; Savitski, M. M.; Fälth Savitski, M; Grandi, P; Hopf, C; Lindon, M; Neubauer, G; Prinjha, R. K.; Bantscheff, M; Drewes, G (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.
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