Clinical trials for BET inhibitors run ahead of the science

Drug Discovery Today: Technologies

Volumn 19, Issue , 2016, Pages 45-50

  Andrieu, Guillaume ^a   Belkina, Anna C ^a   Denis, Gerald V ^a  

^a BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 (4 CHLOROPHENYL) N ETHYL 8 METHOXY 1 METHYL 4H [1,2,4]TRIAZOLO[4,3 A][1,4]BENZODIAZEPINE 4 ACETAMIDE; BIRABRESIB; BROMODOMAIN INHIBITOR; INSULIN; MYC PROTEIN; NUCLEAR PROTEIN; TRANSCRIPTION FACTOR;

ADIPOCYTE; ADIPOGENESIS; CANCER CELL; CANCER THERAPY; CELL DIFFERENTIATION; CELL PROLIFERATION; CLINICAL TRIAL (TOPIC); CYTOKINE PRODUCTION; DRUG SAFETY; GENETIC TRANSCRIPTION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFLAMMATION; LATENT VIRUS INFECTION; MACROPHAGE; NEOPLASM; NONHUMAN; PANCREAS ISLET BETA CELL; REVIEW; SIDE EFFECT; T LYMPHOCYTE; TH17 CELL; TRIPLE NEGATIVE BREAST CANCER; ANIMAL; ANTAGONISTS AND INHIBITORS; IMMUNOLOGY; METABOLISM; NEOPLASMS;

ADIPOCYTES; ANIMALS; HUMANS; INFLAMMATION; INSULIN-SECRETING CELLS; MACROPHAGES; NEOPLASMS; NUCLEAR PROTEINS; TH17 CELLS; TRANSCRIPTION FACTORS;

EID: 84992314131     PISSN: None     EISSN: 17406749     Source Type: Journal    
DOI: 10.1016/j.ddtec.2016.06.004     Document Type: Review

References (48)

1. [1] Denis, G.V., Green, M.R., A novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulator. Genes Dev 10 (1996), 261–271.
2. [2] Haynes, S.R., Dollard, C., Winston, F., Beck, S., Trowsdale, J., Dawid, I.B., The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins. Nucleic Acids Res, 20, 1992, 2603.
3. [3] Dhalluin, C., et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399 (1999), 491–496.
4. [4] Denis, G.V., Bromodomain motifs and scaffolding?. Front Biosci 6 (2001), D1065–D1068.
5. [5] Zeng, L., et al. Selective small molecules blocking HIV-1 Tat and coactivator PCAF association. J Am Chem Soc 127 (2005), 2376–2377.
6. [6] Filippakopoulos, P., et al. Selective inhibition of BET bromodomains. Nature 468 (2010), 1067–1073.
7. [7] Nicodeme, E., et al. Suppression of inflammation by a synthetic histone mimic. Nature 468 (2010), 1119–1123.
8. [8] Dawson, M.A., et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478 (2011), 529–533.
9. [9] Mazo, A.M., et al. The trithorax gene, a trans-acting regulator of the bithorax complex in Drosophila, encodes a protein with zinc-binding domains. Proc Natl Acad Sci U S A 87 (1990), 2112–2116.
10. [10] French, C.A., et al. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 63 (2003), 304–307.
11. [11] Mullard, A., Use of personalized cancer drugs runs ahead of the science. Nature, 2015.
12. [12] Boi, M., et al. The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res 21 (2015), 1628–1638.
13. [13] Mertz, J.A., et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A 108 (2011), 16669–16674.
14. [14] Delmore, J.E., et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146 (2011), 904–917.
15. [15] Belkina, A.C., Denis, G.V., BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer 12 (2012), 465–477.
16. [16] Greenwald, R.J., et al. E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia. Blood 103 (2004), 1475–1484.
17. [17] Lenburg, M.E., et al. Tumor-specific and proliferation-specific gene expression typifies murine transgenic B cell lymphomagenesis. J Biol Chem 282 (2007), 4803–4811.
18. [18] Romesser, P.B., et al. Development of a malignancy-associated proteomic signature for diffuse large B-cell lymphoma. Am J Pathol 175 (2009), 25–35.
19. [19] Bolden, J.E., et al. Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. Cell Rep 8 (2014), 1919–1929.
20. [20] Belkina, A.C., et al. The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis. J Leukoc Biol 95 (2014), 451–460.
21. [21] Shu, S., et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529 (2016), 413–417.
22. [22] Belkina, A.C., et al. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. J Immunol 190 (2013), 3670–3678.
23. [23] Bisgrove, D.A., et al. Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription. Proc Natl Acad Sci U S A 104 (2007), 13690–13695.
24. [24] Banerjee, C., et al. BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol 92 (2012), 1147–1154.
25. [25] Wu, S.Y., et al. Brd4 links chromatin targeting to HPV transcriptional silencing. Genes Dev 20 (2006), 2383–2396.
26. [26] Rahman, S., et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol Cell Biol 31 (2011), 2641–2652.
27. [27] Platt, G.M., et al. Latent nuclear antigen of Kaposi's sarcoma-associated herpesvirus interacts with RING3, a homolog of the Drosophila female sterile homeotic (fsh) gene. J Virol 73 (1999), 9789–9795.
28. [28] Viejo-Borbolla, A., et al. Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. J Virol 79 (2005), 13618–13629.
29. [29] You, J., et al. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol 80 (2006), 8909–8919.
30. [30] Wu, S.Y., et al. Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting. Mol Cell 49 (2013), 843–857.
31. [31] Mele, D.A., et al. BET bromodomain inhibition suppresses TH17-mediated pathology. J Exp Med 210 (2013), 2181–2190.
32. [32] Ip, B., et al. Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNFalpha production. Obesity (Silver Spring) 24 (2016), 102–112.
33. [33] Denis, G.V., et al. Identification of transcription complexes that contain the double bromodomain protein Brd2 and chromatin remodeling machines. J Proteome Res 5 (2006), 502–511.
34. [34] Jiang, Y.W., et al. Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc Natl Acad Sci U S A 95 (1998), 8538–8543.
35. [35] Wang, F., et al. Brd2 disruption in mice causes severe obesity without Type 2 diabetes. Biochem J 425 (2010), 71–83.
36. [36] Wang, F., et al. Brd2 gene disruption causes metabolically healthy obesity: epigenetic and chromatin-based mechanisms that uncouple obesity from type 2 diabetes. Vitam Horm 91 (2013), 49–75.
37. [37] Fu, W., et al. Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and beta cells. Elife, 3, 2014, e04631.
38. [38] Lehuen, A., A double-edged sword against type 1 diabetes. N Engl J Med 372 (2015), 778–780.
39. [39] Lamonica, J.M., et al. Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes. Proc Natl Acad Sci U S A 108 (2011), E159–E168.
40. [40] Renehan, A.G., et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371 (2008), 569–578.
41. [41] Foulkes, W.D., et al. Triple-negative breast cancer. N Engl J Med 363 (2010), 1938–1948.
42. [42] Henssen, A., et al. Targeting MYCN-driven transcription by BET-bromodomain inhibition. Clin Cancer Res 22 (2016), 2470–2481.
43. [43] Maruyama, T., et al. A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase. Mol Cell Biol 22 (2002), 6509–6520.
44. [44] Shi, J., et al. Disrupting the interaction of BRD4 with diacetylated twist suppresses tumorigenesis in basal-like breast cancer. Cancer Cell 25 (2014), 210–225.
45. [45] Matzuk, M.M., et al. Small-molecule inhibition of BRDT for male contraception. Cell 150 (2012), 673–684.
46. [46] Rathert, P., et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525 (2015), 543–547.
47. [47] Raux, B., et al. Exploring selective inhibition of the first bromodomain of the human bromodomain and extra-terminal domain (BET) proteins. J Med Chem 59 (2016), 1634–1641.
48. [48] Butler, D., Callaway, E., Scientists in the dark after French clinical trial proves fatal. Nature 529 (2016), 263–264.