Login Register Cart 0
Generic placeholder image

Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Privileged Scaffolds Targeting Bromodomain-containing Protein 4

Author(s): Ru Wang, Yi-Ang Wang, Yun-Gen Xu* and Lei Shi*

Volume 22, Issue 7, 2022

Published on: 11 March, 2022

Page: [600 - 627] Pages: 28

DOI: 10.2174/1568026622666220209143949

Price: $65

Abstract

In recent years, bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) family, has been one of the most widely studied targets. BRD4 is a transcriptional regulation factor, which regulates cell transcription, marks mammalian biological mitosis, regulates cell cycle, and plays an important role in the biological process of cancer occurrence and development. It has been demonstrated that the imbalance or dysfunction of BRD4 expression leads to various types of cancers, including testicular gene nuclear protein melanoma, acute myeloid leukemia, colon cancer, breast cancer, liver cancer, and midline cancer. Therefore, inhibition of BRD4 has become a valuable approach in the treatment of these cancers. To date, there are numerous BRD4 inhibitors in preclinical development, some of which have entered human clinical trials. In this review, current progress in the development of privileged scaffolds designed as BRD4 inhibitors will be discussed by focusing on structure-activity relationship, selectivity, and mechanisms of action.

Keywords: BRD4, BET, Small molecule inhibitor, Privileged scaffold, Structure-activity relationship, protein.

« Previous
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Chen, H.; Wu, J.; Gao, Y.; Chen, H.; Zhou, J. Scaffold repurposing of old drugs towards new cancer drug discovery. Curr. Top. Med. Chem., 2016, 16(19), 2107-2114.
[http://dx.doi.org/10.2174/1568026616666160216155556] [PMID: 26881709]
[3]
Deep, A.; Bhatia, R.K.; Kaur, R.; Kumar, S.; Jain, U.K.; Singh, H.; Batra, S.; Kaushik, D.; Deb, P.K. Imidazo[1,2-a]pyridine scaffold as prospective therapeutic agents. Curr. Top. Med. Chem., 2017, 17(2), 238-250.
[http://dx.doi.org/10.2174/1568026616666160530153233] [PMID: 27237332]
[4]
de Carvalho da Silva, F.; Ferreira, V.F.; da Silva Magalhães Forezi, L. Synthesis and biological profiles of 1,2,3-Triazole scaffold. Curr. Top. Med. Chem., 2018, 18(17), 1426-1427.
[http://dx.doi.org/10.2174/156802661817181107151553] [PMID: 30497357]
[5]
Guo, H.; Diao, Q.P. The anti-breast cancer potential of bis-isatin scaffolds. Curr. Top. Med. Chem., 2020, 20(16), 1499-1503.
[http://dx.doi.org/10.2174/1568026620666200310124416] [PMID: 32156238]
[6]
Stathis, A.; Bertoni, F. BET proteins as targets for anticancer treatment. Cancer Discov., 2018, 8(1), 24-36.
[http://dx.doi.org/10.1158/2159-8290.CD-17-0605] [PMID: 29263030]
[7]
Jang, M.K.; Mochizuki, K.; Zhou, M.; Jeong, H.S.; Brady, J.N.; Ozato, K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell, 2005, 19(4), 523-534.
[http://dx.doi.org/10.1016/j.molcel.2005.06.027] [PMID: 16109376]
[8]
Liu, Z.; Wang, P.; Chen, H.; Wold, E.A.; Tian, B.; Brasier, A.R.; Zhou, J. Drug discovery targeting bromodomain-containing protein 4. J. Med. Chem., 2017, 60(11), 4533-4558.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01761] [PMID: 28195723]
[9]
Tamkun, J.W.; Deuring, R.; Scott, M.P.; Kissinger, M.; Pattatucci, A.M.; Kaufman, T.C.; Kennison, J.A. Brahma: A regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell, 1992, 68(3), 561-572.
[http://dx.doi.org/10.1016/0092-8674(92)90191-E] [PMID: 1346755]
[10]
Dhalluin, C.; Carlson, J.E.; Zeng, L.; He, C.; Aggarwal, A.K.; Zhou, M.M.; Zhou, M-M. Structure and ligand of a histone acetyltransferase bromodomain. Nature, 1999, 399(6735), 491-496.
[http://dx.doi.org/10.1038/20974] [PMID: 10365964]
[11]
Richardson, J.S. The anatomy and taxonomy of protein structure. Adv. Protein Chem., 1981, 34, 167-339.
[http://dx.doi.org/10.1016/S0065-3233(08)60520-3] [PMID: 7020376]
[12]
Presnell, S.R.; Cohen, F.E. Topological distribution of four-alpha-helix bundles. Proc. Natl. Acad. Sci. USA, 1989, 86(17), 6592-6596.
[http://dx.doi.org/10.1073/pnas.86.17.6592] [PMID: 2771946]
[13]
Filippakopoulos, P.; Picaud, S.; Mangos, M.; Keates, T.; Lambert, J.P.; Barsyte-Lovejoy, D.; Felletar, I.; Volkmer, R.; Müller, S.; Pawson, T.; Gingras, A.C.; Arrowsmith, C.H.; Knapp, S. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell, 2012, 149(1), 214-231.
[http://dx.doi.org/10.1016/j.cell.2012.02.013] [PMID: 22464331]
[14]
Owen, D.J.; Ornaghi, P.; Yang, J.C.; Lowe, N.; Evans, P.R.; Ballario, P.; Neuhaus, D.; Filetici, P.; Travers, A.A. The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p. EMBO J., 2000, 19(22), 6141-6149.
[http://dx.doi.org/10.1093/emboj/19.22.6141] [PMID: 11080160]
[15]
Shi, J.; Vakoc, C.R. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol. Cell, 2014, 54(5), 728-736.
[http://dx.doi.org/10.1016/j.molcel.2014.05.016] [PMID: 24905006]
[16]
Zhang, G.; Smith, S.G.; Zhou, M.M. Discovery of chemical inhibitors of human bromodomains. Chem. Rev., 2015, 115(21), 11625-11668.
[http://dx.doi.org/10.1021/acs.chemrev.5b00205] [PMID: 26492937]
[17]
LeRoy, G.; Rickards, B.; Flint, S.J. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol. Cell, 2008, 30(1), 51-60.
[http://dx.doi.org/10.1016/j.molcel.2008.01.018] [PMID: 18406326]
[18]
Faivre, E.J.; McDaniel, K.F.; Albert, D.H.; Mantena, S.R.; Plotnik, J.P.; Wilcox, D.; Zhang, L.; Bui, M.H.; Sheppard, G.S.; Wang, L.; Sehgal, V.; Lin, X.; Huang, X.; Lu, X.; Uziel, T.; Hessler, P.; Lam, L.T.; Bellin, R.J.; Mehta, G.; Fidanze, S.; Pratt, J.K.; Liu, D.; Hasvold, L.A.; Sun, C.; Panchal, S.C.; Nicolette, J.J.; Fossey, S.L.; Park, C.H.; Longenecker, K.; Bigelow, L.; Torrent, M.; Rosenberg, S.H.; Kati, W.M.; Shen, Y. Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. Nature, 2020, 578(7794), 306-310.
[http://dx.doi.org/10.1038/s41586-020-1930-8] [PMID: 31969702]
[19]
Cheung, K.L.; Zhang, F.; Jaganathan, A.; Sharma, R.; Zhang, Q.; Konuma, T.; Shen, T.; Lee, J.Y.; Ren, C.; Chen, C.H.; Lu, G.; Olson, M.R.; Zhang, W.; Kaplan, M.H.; Littman, D.R.; Walsh, M.J.; Xiong, H.; Zeng, L.; Zhou, M.M. Distinct roles of Brd2 and Brd4 in potentiating the transcriptional program for Th17 cell differentiation. Mol. Cell, 2017, 65(6), 1068-1080.e5.
[http://dx.doi.org/10.1016/j.molcel.2016.12.022] [PMID: 28262505]
[20]
Fujiwara, Y.; Browne, C.P.; Cunniff, K.; Goff, S.C.; Orkin, S.H. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc. Natl. Acad. Sci. USA, 1996, 93(22), 12355-12358.
[http://dx.doi.org/10.1073/pnas.93.22.12355] [PMID: 8901585]
[21]
Shivdasani, R.A.; Fujiwara, Y.; McDevitt, M.A.; Orkin, S.H. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J., 1997, 16(13), 3965-3973.
[http://dx.doi.org/10.1093/emboj/16.13.3965] [PMID: 9233806]
[22]
Yu, C.; Cantor, A.B.; Yang, H.; Browne, C.; Wells, R.A.; Fujiwara, Y.; Orkin, S.H. Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J. Exp. Med., 2002, 195(11), 1387-1395.
[http://dx.doi.org/10.1084/jem.20020656] [PMID: 12045237]
[23]
Migliaccio, A.R.; Rana, R.A.; Sanchez, M.; Lorenzini, R.; Centurione, L.; Bianchi, L.; Vannucchi, A.M.; Migliaccio, G.; Orkin, S.H. GATA-1 as a regulator of mast cell differentiation revealed by the phenotype of the GATA-1low mouse mutant. J. Exp. Med., 2003, 197(3), 281-296.
[http://dx.doi.org/10.1084/jem.20021149] [PMID: 12566412]
[24]
Lamonica, J.M.; Deng, W.; Kadauke, S.; Campbell, A.E.; Gamsjaeger, R.; Wang, H.; Cheng, Y.; Billin, A.N.; Hardison, R.C.; Mackay, J.P.; Blobel, G.A. Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes. Proc. Natl. Acad. Sci. USA, 2011, 108(22), E159-E168.
[http://dx.doi.org/10.1073/pnas.1102140108] [PMID: 21536911]
[25]
Belkina, A.C.; Denis, G.V. BET domain co-regulators in obesity, inflammation and cancer. Nat. Rev. Cancer, 2012, 12(7), 465-477.
[http://dx.doi.org/10.1038/nrc3256] [PMID: 22722403]
[26]
Shao, Z.; Zhang, R.; Khodadadi-Jamayran, A.; Chen, B.; Crowley, M.R.; Festok, M.A.; Crossman, D.K.; Townes, T.M.; Hu, K. The acetyllysine reader BRD3R promotes human nuclear reprogramming and regulates mitosis. Nat. Commun., 2016, 7(1), 10869.
[http://dx.doi.org/10.1038/ncomms10869] [PMID: 26947130]
[27]
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. Suppression of inflammation by a synthetic histone mimic. Nature, 2010, 468(7327), 1119-1123.
[http://dx.doi.org/10.1038/nature09589] [PMID: 21068722]
[28]
Chen, W.; Han, C.; Xie, B.; Hu, X.; Yu, Q.; Shi, L.; Wang, Q.; Li, D.; Wang, J.; Zheng, P.; Liu, Y.; Cao, X. Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation. Cell, 2013, 152(3), 467-478.
[http://dx.doi.org/10.1016/j.cell.2013.01.011] [PMID: 23374343]
[29]
Bryant, C.E.; Symmons, M.; Gay, N.J. Toll-like receptor signalling through macromolecular protein complexes. Mol. Immunol., 2015, 63(2), 162-165.
[http://dx.doi.org/10.1016/j.molimm.2014.06.033] [PMID: 25081091]
[30]
Tanaka, T.; Kishimoto, T. The biology and medical implications of interleukin-6. Cancer Immunol. Res., 2014, 2(4), 288-294.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0022] [PMID: 24764575]
[31]
Masumi, A. Histone acetyltransferases as regulators of nonhistone proteins: The role of interferon regulatory factor acetylation on gene transcription. J. Biomed. Biotechnol., 2011, 2011, 640610.
[http://dx.doi.org/10.1155/2011/640610] [PMID: 21234331]
[32]
Zhang, Q.; Zhao, K.; Shen, Q.; Han, Y.; Gu, Y.; Li, X.; Zhao, D.; Liu, Y.; Wang, C.; Zhang, X.; Su, X.; Liu, J.; Ge, W.; Levine, R.L.; Li, N.; Cao, X. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature, 2015, 525(7569), 389-393.
[http://dx.doi.org/10.1038/nature15252] [PMID: 26287468]
[33]
Ren, W.; Sun, D.; Wang, C.; Li, N. [Brd3 promotes IL-6 production via enhancing acetylase CBP recruitment and histone 3 acetylation within IL6 promoter]. Xibao Yu Fenzi Mianyixue Zazhi, 2016, 32(10), 1301-1305.
[PMID: 27667451]
[34]
Huang, Y.; Nahar, S.; Nakagawa, A.; Fernandez-Barrena, M.G.; Mertz, J.A.; Bryant, B.M.; Adams, C.E.; Mino-Kenudson, M.; Von Alt, K.N.; Chang, K.; Conery, A.R.; Hatton, C.; Sims, R.J., III; Fernandez-Zapico, M.E.; Wang, X.; Lillemoe, K.D.; Fernández-Del Castillo, C.; Warshaw, A.L.; Thayer, S.P.; Liss, A.S. Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment. Clin. Cancer Res., 2016, 22(16), 4259-4270.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2068] [PMID: 27169995]
[35]
Gaucher, J.; Boussouar, F.; Montellier, E.; Curtet, S.; Buchou, T.; Bertrand, S.; Hery, P.; Jounier, S.; Depaux, A.; Vitte, A.L.; Guardiola, P.; Pernet, K.; Debernardi, A.; Lopez, F.; Holota, H.; Imbert, J.; Wolgemuth, D.J.; Gérard, M.; Rousseaux, S.; Khochbin, S. Bromodomain-dependent stage-specific male genome programming by Brdt. EMBO J., 2012, 31(19), 3809-3820.
[http://dx.doi.org/10.1038/emboj.2012.233] [PMID: 22922464]
[36]
Feichtinger, J.; Aldeailej, I.; Anderson, R.; Almutairi, M.; Almatrafi, A.; Alsiwiehri, N.; Griffiths, K.; Stuart, N.; Wakeman, J.A.; Larcombe, L.; McFarlane, R.J. Meta-analysis of clinical data using human meiotic genes identifies a novel cohort of highly restricted cancer-specific marker genes. Oncotarget, 2012, 3(8), 843-853.
[http://dx.doi.org/10.18632/oncotarget.580] [PMID: 22918178]
[37]
Rousseaux, S.; Debernardi, A.; Jacquiau, B.; Vitte, A.L.; Vesin, A.; Nagy-Mignotte, H.; Moro-Sibilot, D.; Brichon, P.Y.; Lantuejoul, S.; Hainaut, P.; Laffaire, J.; de Reyniès, A.; Beer, D.G.; Timsit, J.F.; Brambilla, C.; Brambilla, E.; Khochbin, S. Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers. Sci. Transl. Med., 2013, 5(186), 186ra66.
[http://dx.doi.org/10.1126/scitranslmed.3005723] [PMID: 23698379]
[38]
Pivot-Pajot, C.; Caron, C.; Govin, J.; Vion, A.; Rousseaux, S.; Khochbin, S. Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein. Mol. Cell. Biol., 2003, 23(15), 5354-5365.
[http://dx.doi.org/10.1128/MCB.23.15.5354-5365.2003] [PMID: 12861021]
[39]
Scanlan, M.J.; Altorki, N.K.; Gure, A.O.; Williamson, B.; Jungbluth, A.; Chen, Y.T.; Old, L.J. Expression of cancer-testis antigens in lung cancer: Definition of bromodomain testis-specific gene (BRDT) as a new CT gene, CT9. Cancer Lett., 2000, 150(2), 155-164.
[http://dx.doi.org/10.1016/S0304-3835(99)00385-7] [PMID: 10704737]
[40]
Bourova-Flin, E.; Chuffart, F.; Rousseaux, S.; Khochbin, S. The role of bromodomain testis-specific factor, BRDT, in cancer: A biomarker and a possible therapeutic target. Cell J., 2017, 19(Suppl. 1), 1-8.
[PMID: 28580303]
[41]
Wu, S.Y.; Chiang, C.M. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J. Biol. Chem., 2007, 282(18), 13141-13145.
[http://dx.doi.org/10.1074/jbc.R700001200] [PMID: 17329240]
[42]
Floyd, S.R.; Pacold, M.E.; Huang, Q.; Clarke, S.M.; Lam, F.C.; Cannell, I.G.; Bryson, B.D.; Rameseder, J.; Lee, M.J.; Blake, E.J.; Fydrych, A.; Ho, R.; Greenberger, B.A.; Chen, G.C.; Maffa, A.; Del Rosario, A.M.; Root, D.E.; Carpenter, A.E.; Hahn, W.C.; Sabatini, D.M.; Chen, C.C.; White, F.M.; Bradner, J.E.; Yaffe, M.B. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature, 2013, 498(7453), 246-250.
[http://dx.doi.org/10.1038/nature12147] [PMID: 23728299]
[43]
Zawistowski, J.S.; Bevill, S.M.; Goulet, D.R.; Stuhlmiller, T.J.; Beltran, A.S.; Olivares-Quintero, J.F.; Singh, D.; Sciaky, N.; Parker, J.S.; Rashid, N.U.; Chen, X.; Duncan, J.S.; Whittle, M.C.; Angus, S.P.; Velarde, S.H.; Golitz, B.T.; He, X.; Santos, C.; Darr, D.B.; Gallagher, K.; Graves, L.M.; Perou, C.M.; Carey, L.A.; Earp, H.S.; Johnson, G.L. Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex. Cancer Discov., 2017, 7(3), 302-321.
[http://dx.doi.org/10.1158/2159-8290.CD-16-0653] [PMID: 28108460]
[44]
Jiang, Y.W.; Veschambre, P.; Erdjument-Bromage, H.; Tempst, P.; Conaway, J.W.; Conaway, R.C.; Kornberg, R.D. Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc. Natl. Acad. Sci. USA, 1998, 95(15), 8538-8543.
[http://dx.doi.org/10.1073/pnas.95.15.8538] [PMID: 9671713]
[45]
Yang, Z.; Yik, J.H.; Chen, R.; He, N.; Jang, M.K.; Ozato, K.; Zhou, Q. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell, 2005, 19(4), 535-545.
[http://dx.doi.org/10.1016/j.molcel.2005.06.029] [PMID: 16109377]
[46]
Bisgrove, D.A.; Mahmoudi, T.; Henklein, P.; Verdin, E. Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription. Proc. Natl. Acad. Sci. USA, 2007, 104(34), 13690-13695.
[http://dx.doi.org/10.1073/pnas.0705053104] [PMID: 17690245]
[47]
Schröder, S.; Cho, S.; Zeng, L.; Zhang, Q.; Kaehlcke, K.; Mak, L.; Lau, J.; Bisgrove, D.; Schnölzer, M.; Verdin, E.; Zhou, M.M.; Ott, M. Two-pronged binding with bromodomain-containing protein 4 liberates positive transcription elongation factor b from inactive ribonucleoprotein complexes. J. Biol. Chem., 2012, 287(2), 1090-1099.
[http://dx.doi.org/10.1074/jbc.M111.282855] [PMID: 22084242]
[48]
Zhou, Q.; Li, T.; Price, D.H. RNA polymerase II elongation control. Annu. Rev. Biochem., 2012, 81(1), 119-143.
[http://dx.doi.org/10.1146/annurev-biochem-052610-095910] [PMID: 22404626]
[49]
Peng, J.; Zhu, Y.; Milton, J.T.; Price, D.H. Identification of multiple cyclin subunits of human P-TEFb. Genes Dev., 1998, 12(5), 755-762.
[http://dx.doi.org/10.1101/gad.12.5.755] [PMID: 9499409]
[50]
Yang, Z.; He, N.; Zhou, Q. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol. Cell. Biol., 2008, 28(3), 967-976.
[http://dx.doi.org/10.1128/MCB.01020-07] [PMID: 18039861]
[51]
Sakurai, N.; Inamochi, Y.; Inoue, T.; Hariya, N.; Kawamura, M.; Yamada, M.; Dey, A.; Nishiyama, A.; Kubota, T.; Ozato, K.; Goda, T.; Mochizuki, K. BRD4 regulates adiponectin gene induction by recruiting the P-TEFb complex to the transcribed region of the gene. Sci. Rep., 2017, 7(1), 11962.
[http://dx.doi.org/10.1038/s41598-017-12342-2] [PMID: 28931940]
[52]
Inamochi, Y.; Dey, A.; Nishiyama, A.; Kubota, T.; Ozato, K.; Goda, T.; Mochizuki, K. Transcription elongation factor Brd4-P-TEFb accelerates intestinal differentiation-associated SLC2A5 gene expression. Biochem. Biophys. Rep., 2016, 7, 150-156.
[http://dx.doi.org/10.1016/j.bbrep.2016.05.016] [PMID: 28955901]
[53]
Konuma, T.; Yu, D.; Zhao, C.; Ju, Y.; Sharma, R.; Ren, C.; Zhang, Q.; Zhou, M.M.; Zeng, L. Structural mechanism of the oxygenase JMJD6 recognition by the Extra-terminal (ET) domain of BRD4. Sci. Rep., 2017, 7(1), 16272.
[http://dx.doi.org/10.1038/s41598-017-16588-8] [PMID: 29176719]
[54]
Smith, R.; Sellou, H.; Chapuis, C.; Huet, S.; Timinszky, G. CHD3 and CHD4 recruitment and chromatin remodeling activity at DNA breaks is promoted by early poly(ADP-ribose)-dependent chromatin relaxation. Nucleic Acids Res., 2018, 46(12), 6087-6098.
[http://dx.doi.org/10.1093/nar/gky334] [PMID: 29733391]
[55]
Larsen, D.H.; Poinsignon, C.; Gudjonsson, T.; Dinant, C.; Payne, M.R.; Hari, F.J.; Rendtlew Danielsen, J.M.; Menard, P.; Sand, J.C.; Stucki, M.; Lukas, C.; Bartek, J.; Andersen, J.S.; Lukas, J. The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage. J. Cell Biol., 2010, 190(5), 731-740.
[http://dx.doi.org/10.1083/jcb.200912135] [PMID: 20805324]
[56]
Rahman, S.; Sowa, M.E.; Ottinger, M.; Smith, J.A.; Shi, Y.; Harper, J.W.; Howley, P.M. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol. Cell. Biol., 2011, 31(13), 2641-2652.
[http://dx.doi.org/10.1128/MCB.01341-10] [PMID: 21555454]
[57]
Zhang, Q.; Zeng, L.; Shen, C.; Ju, Y.; Konuma, T.; Zhao, C.; Vakoc, C.R.; Zhou, M.M. Structural mechanism of transcriptional regulator NSD3 recognition by the ET Domain of BRD4. Structure, 2016, 24(7), 1201-1208.
[http://dx.doi.org/10.1016/j.str.2016.04.019] [PMID: 27291650]
[58]
Liu, W.; Ma, Q.; Wong, K.; Li, W.; Ohgi, K.; Zhang, J.; Aggarwal, A.; Rosenfeld, M.G. Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release. Cell, 2013, 155(7), 1581-1595.
[http://dx.doi.org/10.1016/j.cell.2013.10.056] [PMID: 24360279]
[59]
Conrad, R.J.; Fozouni, P.; Thomas, S.; Sy, H.; Zhang, Q.; Zhou, M.M.; Ott, M. The short isoform of brd4 promotes hiv-1 latency by engaging repressive swi/snf chromatin-remodeling complexes. Mol. Cell, 2017, 67(6), 1001-1012.e6.
[http://dx.doi.org/10.1016/j.molcel.2017.07.025] [PMID: 28844864]
[60]
Fukazawa, H.; Masumi, A. The conserved 12-amino acid stretch in the inter-bromodomain region of BET family proteins functions as a nuclear localization signal. Biol. Pharm. Bull., 2012, 35(11), 2064-2068.
[http://dx.doi.org/10.1248/bpb.b12-00527] [PMID: 22971749]
[61]
Dey, A.; Chitsaz, F.; Abbasi, A.; Misteli, T.; Ozato, K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc. Natl. Acad. Sci. USA, 2003, 100(15), 8758-8763.
[http://dx.doi.org/10.1073/pnas.1433065100] [PMID: 12840145]
[62]
Huang, B.; Yang, X.D.; Zhou, M.M.; Ozato, K.; Chen, L.F. Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA. Mol. Cell. Biol., 2009, 29(5), 1375-1387.
[http://dx.doi.org/10.1128/MCB.01365-08] [PMID: 19103749]
[63]
French, C.A. NUT midline carcinoma. Cancer Genet. Cytogenet., 2010, 203(1), 16-20.
[http://dx.doi.org/10.1016/j.cancergencyto.2010.06.007] [PMID: 20951314]
[64]
French, C.A. Pathogenesis of NUT midline carcinoma. Annu. Rev. Pathol., 2012, 7(1), 247-265.
[http://dx.doi.org/10.1146/annurev-pathol-011811-132438] [PMID: 22017582]
[65]
Bauer, D.E.; Mitchell, C.M.; Strait, K.M.; Lathan, C.S.; Stelow, E.B.; Lüer, S.C.; Muhammed, S.; Evans, A.G.; Sholl, L.M.; Rosai, J.; Giraldi, E.; Oakley, R.P.; Rodriguez-Galindo, C.; London, W.B.; Sallan, S.E.; Bradner, J.E.; French, C.A. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin. Cancer Res., 2012, 18(20), 5773-5779.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-1153] [PMID: 22896655]
[66]
French, C.A.; Miyoshi, I.; Kubonishi, I.; Grier, H.E.; Perez-Atayde, A.R.; Fletcher, J.A. BRD4-NUT fusion oncogene: A novel mechanism in aggressive carcinoma. Cancer Res., 2003, 63(2), 304-307.
[PMID: 12543779]
[67]
French, C.A.; Ramirez, C.L.; Kolmakova, J.; Hickman, T.T.; Cameron, M.J.; Thyne, M.E.; Kutok, J.L.; Toretsky, J.A.; Tadavarthy, A.K.; Kees, U.R.; Fletcher, J.A.; Aster, J.C. BRD-NUT oncoproteins: A family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene, 2008, 27(15), 2237-2242.
[http://dx.doi.org/10.1038/sj.onc.1210852] [PMID: 17934517]
[68]
Wang, R.; You, J. Mechanistic analysis of the role of bromodomain-containing protein 4 (BRD4) in BRD4-NUT oncoprotein-induced transcriptional activation. J. Biol. Chem., 2015, 290(5), 2744-2758.
[http://dx.doi.org/10.1074/jbc.M114.600759] [PMID: 25512383]
[69]
Crawford, N.P.; Alsarraj, J.; Lukes, L.; Walker, R.C.; Officewala, J.S.; Yang, H.H.; Lee, M.P.; Ozato, K.; Hunter, K.W. Bromodomain 4 activation predicts breast cancer survival. Proc. Natl. Acad. Sci. USA, 2008, 105(17), 6380-6385.
[http://dx.doi.org/10.1073/pnas.0710331105] [PMID: 18427120]
[70]
Crawford, N.P.; Walker, R.C.; Lukes, L.; Officewala, J.S.; Williams, R.W.; Hunter, K.W. The Diasporin Pathway: A tumor progression-related transcriptional network that predicts breast cancer survival. Clin. Exp. Metastasis, 2008, 25(4), 357-369.
[http://dx.doi.org/10.1007/s10585-008-9146-6] [PMID: 18301994]
[71]
Alsarraj, J.; Walker, R.C.; Webster, J.D.; Geiger, T.R.; Crawford, N.P.; Simpson, R.M.; Ozato, K.; Hunter, K.W. Deletion of the proline-rich region of the murine metastasis susceptibility gene Brd4 promotes epithelial-to-mesenchymal transition- and stem cell-like conversion. Cancer Res., 2011, 71(8), 3121-3131.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-4417] [PMID: 21389092]
[72]
Desmond, J.C.; Raynaud, S.; Tung, E.; Hofmann, W.K.; Haferlach, T.; Koeffler, H.P. Discovery of epigenetically silenced genes in acute myeloid leukemias. Leukemia, 2007, 21(5), 1026-1034.
[http://dx.doi.org/10.1038/sj.leu.2404611] [PMID: 17330099]
[73]
Wong, P.; Iwasaki, M.; Somervaille, T.C.; Ficara, F.; Carico, C.; Arnold, C.; Chen, C.Z.; Cleary, M.L. The miR-17-92 microRNA polycistron regulates MLL leukemia stem cell potential by modulating p21 expression. Cancer Res., 2010, 70(9), 3833-3842.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3268] [PMID: 20406979]
[74]
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. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature, 2011, 478(7370), 524-528.
[http://dx.doi.org/10.1038/nature10334] [PMID: 21814200]
[75]
Lenhart, R.; Kirov, S.; Desilva, H.; Cao, J.; Lei, M.; Johnston, K.; Peterson, R.; Schweizer, L.; Purandare, A.; Ross-Macdonald, P.; Fairchild, C.; Wong, T.; Wee, S. Sensitivity of small cell lung cancer to BET inhibition is mediated by regulation of ASCL1 gene expression. Mol. Cancer Ther., 2015, 14(10), 2167-2174.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0037] [PMID: 26253517]
[76]
Liu, Y.; Li, Y.; Liu, S.; Adeegbe, D.O.; Christensen, C.L.; Quinn, M.M.; Dries, R.; Han, S.; Buczkowski, K.; Wang, X.; Chen, T.; Gao, P.; Zhang, H.; Li, F.; Hammerman, P.S.; Bradner, J.E.; Quayle, S.N.; Wong, K.K. NK cells mediate synergistic antitumor effects of combined inhibition of HDAC6 and BET in a SCLC preclinical model. Cancer Res., 2018, 78(13), 3709-3717.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-0161] [PMID: 29760044]
[77]
Lam, L.T.; Lin, X.; Faivre, E.J.; Yang, Z.; Huang, X.; Wilcox, D.M.; Bellin, R.J.; Jin, S.; Tahir, S.K.; Mitten, M.; Magoc, T.; Bhathena, A.; Kati, W.M.; Albert, D.H.; Shen, Y.; Uziel, T. Vulnerability of small cell lung cancer to apoptosis induced by the combination of BET bromodomain proteins and BCL2 inhibitors. Mol. Cancer Ther., 2017, 16(8), 1511-1520.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0459] [PMID: 28468776]
[78]
Li, G.Q.; Guo, W.Z.; Zhang, Y.; Seng, J.J.; Zhang, H.P.; Ma, X.X.; Zhang, G.; Li, J.; Yan, B.; Tang, H.W.; Li, S.S.; Wang, L.D.; Zhang, S.J. Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression. Oncotarget, 2016, 7(3), 2462-2474.
[http://dx.doi.org/10.18632/oncotarget.6275] [PMID: 26575167]
[79]
He, L.; Meng, D.; Zhang, S.H.; Zhang, Y.; Deng, Z.; Kong, L.B. microRNA-608 inhibits human hepatocellular carcinoma cell proliferation via targeting the BET family protein BRD4. Biochem. Biophys. Res. Commun., 2018, 501(4), 1060-1067.
[http://dx.doi.org/10.1016/j.bbrc.2018.05.108] [PMID: 29777702]
[80]
Segura, M.F.; Fontanals-Cirera, B.; Gaziel-Sovran, A.; Guijarro, M.V.; Hanniford, D.; Zhang, G.; González-Gomez, P.; Morante, M.; Jubierre, L.; Zhang, W.; Darvishian, F.; Ohlmeyer, M.; Osman, I.; Zhou, M.M.; Hernando, E. BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapy. Cancer Res., 2013, 73(20), 6264-6276.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-0122-T] [PMID: 23950209]
[81]
Tan, Y.; Wang, L.; Du, Y.; Liu, X.; Chen, Z.; Weng, X.; Guo, J.; Chen, H.; Wang, M.; Wang, X. Inhibition of BRD4 suppresses tumor growth in prostate cancer via the enhancement of FOXO1 expression. Int. J. Oncol., 2018, 53(6), 2503-2517.
[http://dx.doi.org/10.3892/ijo.2018.4577] [PMID: 30272279]
[82]
Rodriguez, R.M.; Huidobro, C.; Urdinguio, R.G.; Mangas, C.; Soldevilla, B.; Domínguez, G.; Bonilla, F.; Fernandez, A.F.; Fraga, M.F. Aberrant epigenetic regulation of bromodomain BRD4 in human colon cancer. J. Mol. Med. (Berl.), 2012, 90(5), 587-595.
[http://dx.doi.org/10.1007/s00109-011-0837-0] [PMID: 22120039]
[83]
Yu, L.; Wang, Z.; Zhang, Z.; Ren, X.; Lu, X.; Ding, K. Small-molecule BET inhibitors in clinical and preclinical development and their therapeutic potential. Curr. Top. Med. Chem., 2015, 15(8), 776-794.
[http://dx.doi.org/10.2174/1568026615666150302110135] [PMID: 25732788]
[84]
Zhao, L.; Duan, Y.T.; Lu, P.; Zhang, Z.J.; Zheng, X.K.; Wang, J.L.; Feng, W.S. Epigenetic targets and their inhibitors in cancer therapy. Curr. Top. Med. Chem., 2018, 18(28), 2395-2419.
[http://dx.doi.org/10.2174/1568026619666181224095449] [PMID: 30582481]
[85]
Yang, A.Y.; Kim, H.; Li, W.; Kong, A.N. Natural compound-derived epigenetic regulators targeting epigenetic readers, writers and erasers. Curr. Top. Med. Chem., 2016, 16(7), 697-713.
[http://dx.doi.org/10.2174/1568026615666150826114359] [PMID: 26306989]
[86]
Duan, Y.T.; Sangani, C.B.; Liu, W.; Soni, K.V.; Yao, Y. New promises to cure cancer and other genetic diseases/disorders: Epi-drugs through epigenetics. Curr. Top. Med. Chem., 2019, 19(12), 972-994.
[http://dx.doi.org/10.2174/1568026619666190603094439] [PMID: 31161992]
[87]
Liu, W.; Wang, X.; Zhu, H.; Duan, Y. Precision tumor medicine and drug targets. Curr. Top. Med. Chem., 2019, 19(17), 1488-1489.
[http://dx.doi.org/10.2174/156802661917190828111130] [PMID: 31592750]
[88]
Sachchidanand, R-S.L.; Resnick-Silverman, L.; Yan, S.; Mutjaba, S.; Liu, W.J.; Zeng, L.; Manfredi, J.J.; Zhou, M.M. Target structure-based discovery of small molecules that block human p53 and CREB binding protein association. Chem. Biol., 2006, 13(1), 81-90.
[http://dx.doi.org/10.1016/j.chembiol.2005.10.014] [PMID: 16426974]
[89]
Gacias, M.; Gerona-Navarro, G.; Plotnikov, A.N.; Zhang, G.; Zeng, L.; Kaur, J.; Moy, G.; Rusinova, E.; Rodriguez, Y.; Matikainen, B.; Vincek, A.; Joshua, J.; Casaccia, P.; Zhou, M.M. Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem. Biol., 2014, 21(7), 841-854.
[http://dx.doi.org/10.1016/j.chembiol.2014.05.009] [PMID: 24954007]
[90]
Borah, J.C.; Mujtaba, S.; Karakikes, I.; Zeng, L.; Muller, M.; Patel, J.; Moshkina, N.; Morohashi, K.; Zhang, W.; Gerona-Navarro, G.; Hajjar, R.J.; Zhou, M.M. A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes. Chem. Biol., 2011, 18(4), 531-541.
[http://dx.doi.org/10.1016/j.chembiol.2010.12.021] [PMID: 21513889]
[91]
Zhang, G.; Plotnikov, A.N.; Rusinova, E.; Shen, T.; Morohashi, K.; Joshua, J.; Zeng, L.; Mujtaba, S.; Ohlmeyer, M.; Zhou, M.M. Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains. J. Med. Chem., 2013, 56(22), 9251-9264.
[http://dx.doi.org/10.1021/jm401334s] [PMID: 24144283]
[92]
Zhou, M.M.; Ohlmeyer, M.; Mujtaba, S.; Plotnikov, A.; Kastrinsky, D.; Zhang, G.; Borah, J.C. Inhibitors of bromodomains as modulators of gene expression. WO Patent 2012116170, 2012.
[93]
Di Micco, R.; Fontanals-Cirera, B.; Low, V.; Ntziachristos, P.; Yuen, S.K.; Lovell, C.D.; Dolgalev, I.; Yonekubo, Y.; Zhang, G.; Rusinova, E.; Gerona-Navarro, G.; Cañamero, M.; Ohlmeyer, M.; Aifantis, I.; Zhou, M.M.; Tsirigos, A.; Hernando, E. Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep., 2014, 9(1), 234-247.
[http://dx.doi.org/10.1016/j.celrep.2014.08.055] [PMID: 25263550]
[94]
Zhou, J.; Brasier, A.; Tian, B.; Liu, Z.; Chen, H.; Rytting, E. Inhibitors of bromodomain-containing protein 4 (BRD4). WO Patent 2018112037, 2018.
[95]
Liu, Z.; Tian, B.; Chen, H.; Wang, P.; Brasier, A.R.; Zhou, J. Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation. Eur. J. Med. Chem., 2018, 151, 450-461.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.006] [PMID: 29649741]
[96]
Brasier, A.; Sur, S.; Zhou, J.; Tian, B. BRD4 inhibitor treatment of IGE-mediated diseases. U.S. Patent 2019381013, 2019.
[97]
Smith, S.G.; Sanchez, R.; Zhou, M.M. Privileged diazepine compounds and their emergence as bromodomain inhibitors. Chem. Biol., 2014, 21(5), 573-583.
[http://dx.doi.org/10.1016/j.chembiol.2014.03.004] [PMID: 24746559]
[98]
Randino, R.; Moronese, I.; Cini, E.; Bizzarro, V.; Persico, M.; Grimaldi, M.; Scrima, M.; D’Ursi, A.M.; Novellino, E.; Sobarzo-Sanchez, E.; Rastrelli, L.; Fattorusso, C.; Petrella, A.; Rodriquez, M.; Taddei, M. Benzodiazepine scaffold as drug-like molecular simplification of FR235222: A chemical tool for exploring HDAC inhibition. Curr. Top. Med. Chem., 2017, 17(4), 441-459.
[PMID: 27558677]
[99]
Sigel, E.; Lüscher, B.P. A closer look at the high affinity benzodiazepine binding site on GABAA receptors. Curr. Top. Med. Chem., 2011, 11(2), 241-246.
[http://dx.doi.org/10.2174/156802611794863562] [PMID: 21189125]
[100]
Muylaert, K.; Jatczak, M.; Mangelinckx, S.; Stevens, C.V. Synthesis of pyrido-annelated diazepines, oxazepines and thiazepines. Curr. Med. Chem., 2016, 23(42), 4784-4823.
[http://dx.doi.org/10.2174/0929867323666160920101332] [PMID: 27655072]
[101]
Miyoshi, S.; Ooike, S.; Iwata, K.; Hikawa, H.; Sugahara, K. Thienotriazolodiazepine compounds for use in the treatment or prevention of cancder. WO Patent 2009084693, 2011.
[102]
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. Selective inhibition of BET bromodomains. Nature, 2010, 468(7327), 1067-1073.
[http://dx.doi.org/10.1038/nature09504] [PMID: 20871596]
[103]
Braun, T.; Coude, M.M.; Berrou, J.; Bertrand, S.; Riveiro, E.; Herait, P.; Baruchel, A.; Dombret, H.; Gardin, C. Preclinical study of the bromodomain inhibitor OTX015 in acute myeloid (Aml) and lymphoid (All) leukemias. Blood, 2013, 122(21), 4218.
[http://dx.doi.org/10.1182/blood.V122.21.4218.4218]
[104]
Noel, J.K.; Iwata, K.; Ooike, S.; Sugahara, K.; Nakamura, H.; Daibata, M. Development of the BET bromodomain inhibitor OTX015. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, Boston, MA. Philadelphia (PA), AACR, Oct 19-23, 2013 Mol. Cancer Ther; , 2013; 12, . (11 Suppl) Abstract nr C244
[105]
Wu, X.; Sebastian, Y.; Shi, Z.; Huynh, M.; Chong, J.; Hwang, S.T. 693 BET inhibitor OTX015 reduces imiquimod-induced mouse psoriasiform dermatitis. J. Invest. Dermatol., 2019, 139(5), S119.
[http://dx.doi.org/10.1016/j.jid.2019.03.769] [PMID: 30468739]
[106]
Devaiah, B.N.; Lewis, B.A.; Cherman, N.; Hewitt, M.C.; Albrecht, B.K.; Robey, P.G.; Ozato, K.; Sims, R.J., III; Singer, D.S. BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc. Natl. Acad. Sci. USA, 2012, 109(18), 6927-6932.
[http://dx.doi.org/10.1073/pnas.1120422109] [PMID: 22509028]
[107]
Zhang, G.; Liu, R.; Zhong, Y.; Plotnikov, A.N.; Zhang, W.; Zeng, L.; Rusinova, E.; Gerona-Nevarro, G.; Moshkina, N.; Joshua, J.; Chuang, P.Y.; Ohlmeyer, M.; He, J.C.; Zhou, M.M. Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J. Biol. Chem., 2012, 287(34), 28840-28851.
[http://dx.doi.org/10.1074/jbc.M112.359505] [PMID: 22645123]
[108]
Griguolo, G.; Stathis, A. BET inhibitors as potential anticancer agents. Drugs Future, 2015, 40(6), 381-388.
[http://dx.doi.org/10.1358/dof.2015.040.06.2319323]
[109]
Camero, S.; Camicia, L.; Marampon, F.; Ceccarelli, S.; Shukla, R.; Mannarino, O.; Pizer, B.; Schiavetti, A.; Pizzuti, A.; Tombolini, V.; Marchese, C.; Dominici, C.; Megiorni, F. BET inhibition therapy counteracts cancer cell survival, clonogenic potential and radioresistance mechanisms in rhabdomyosarcoma cells. Cancer Lett., 2020, 479, 71-88.
[http://dx.doi.org/10.1016/j.canlet.2020.03.011] [PMID: 32200036]
[110]
Landau, S.B.; Kagey, M. Bromodomain inhibitors. WO Patent 2016069578, 2016.
[111]
Endo, J.; Hikawa, H.; Hamada, M.; Ishibuchi, S.; Fujie, N.; Sugiyama, N.; Tanaka, M.; Kobayashi, H.; Sugahara, K.; Oshita, K.; Iwata, K.; Ooike, S.; Murata, M.; Sumichika, H.; Chiba, K.; Adachi, K. A phenotypic drug discovery study on thienodiazepine derivatives as inhibitors of T cell proliferation induced by CD28 co-stimulation leads to the discovery of a first bromodomain inhibitor. Bioorg. Med. Chem. Lett., 2016, 26(5), 1365-1370.
[http://dx.doi.org/10.1016/j.bmcl.2016.01.084] [PMID: 26869194]
[112]
Qian, Y.; Dong, H.; Wang, J.; Berlin, M.; Siu, K.; Crew, A.P.; Crews, C.M. Compounds and methods for the targeted degradation of bromodomain-containing proteins. WO Patent 2017030814, 2017.
[113]
Bradner, J.; Buckley, D.; Winter, G. Methods to induce targeted protein degradation through bifunctional molecules. U.S. Patent 2019151457, 2019.
[114]
Crews, C.M.; Burslem, G.; Cromm, P.M.; Jaime-Figueroa, S.; Toure, M. Imide-based modulators of proteolysis and methods of use. WO Patent 2019148055, 2019.
[115]
Blake, R.A.; Dragovich, P.; Gazzard, L.J.; Kaufman, S.; Kleinheinz, T.; Pillow, T.; Staben, S.; Wei, B. Tert-butyl (S)-2-(4-(phenyl)-6H-thieno [3,2-F] [l,2,4] triazolo [4,3-A] [l,4] diazepin-6-yl) acetate derivatives and related compounds as bromodomain BRD4 inhibitors for treating cancer. WO Patent 2020055976, 2020.
[116]
Xue, G.; Wang, K.; Zhou, D.; Zhong, H.; Pan, Z. Light-induced protein degradation with photocaged PROTACs. J. Am. Chem. Soc., 2019, 141(46), 18370-18374.
[http://dx.doi.org/10.1021/jacs.9b06422] [PMID: 31566962]
[117]
He, S.; Dong, G.; Li, Y.; Wu, S.; Wang, W.; Sheng, C. Potent dual BET/HDAC inhibitors for efficient treatment of pancreatic cancer. Angew. Chem. Int. Ed. Engl., 2020, 59(8), 3028-3032.
[http://dx.doi.org/10.1002/anie.201915896] [PMID: 31943585]
[118]
Mingzhu, Y.; Ying, G.; Rui, H.; Wesley, L.; Yao, L.; Shiyao, P.; Hongyin, S.; Cong, P.; Jiali, L.; Rui, Y.; Qiaohong, Y.; Nenghui, W.; Yongguang, T.; Xiang, C.; Qin, Y. Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. Nat. Commun., 2020, 18, 3311.
[119]
Mirguet, O.; Gosmini, R.; Toum, J.; Clément, C.A.; Barnathan, M.; Brusq, J.M.; Mordaunt, J.E.; Grimes, R.M.; Crowe, M.; Pineau, O.; Ajakane, M.; Daugan, A.; Jeffrey, P.; Cutler, L.; Haynes, A.C.; Smithers, N.N.; Chung, C.W.; Bamborough, P.; Uings, I.J.; Lewis, A.; Witherington, J.; Parr, N.; Prinjha, R.K.; Nicodème, E. Discovery of epigenetic regulator I-BET762: Lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J. Med. Chem., 2013, 56(19), 7501-7515.
[http://dx.doi.org/10.1021/jm401088k] [PMID: 24015967]
[120]
Conway, S.J.; Gardiner, J.; Grove, S.J.; Johns, M.K.; Lim, Z.Y.; Painter, G.F.; Robinson, D.E.; Schieber, C.; Thuring, J.W.; Wong, L.S.; Yin, M.X.; Burgess, A.W.; Catimel, B.; Hawkins, P.T.; Ktistakis, N.T.; Stephens, L.R.; Holmes, A.B. Synthesis and biological evaluation of phosphatidylinositol phosphate affinity probes. Org. Biomol. Chem., 2010, 8(1), 66-76.
[http://dx.doi.org/10.1039/B913399B] [PMID: 20024134]
[121]
Adams, N.D.; Adams, J.L.; Burgess, J.L.; Chaudhari, A.M.; Copeland, R.A.; Donatelli, C.A.; Drewry, D.H.; Fisher, K.E.; Hamajima, T.; Hardwicke, M.A.; Huffman, W.F.; Koretke-Brown, K.K.; Lai, Z.V.; McDonald, O.B.; Nakamura, H.; Newlander, K.A.; Oleykowski, C.A.; Parrish, C.A.; Patrick, D.R.; Plant, R.; Sarpong, M.A.; Sasaki, K.; Schmidt, S.J.; Silva, D.J.; Sutton, D.; Tang, J.; Thompson, C.S.; Tummino, P.J.; Wang, J.C.; Xiang, H.; Yang, J.; Dhanak, D. Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. J. Med. Chem., 2010, 53(10), 3973-4001.
[http://dx.doi.org/10.1021/jm901870q] [PMID: 20420387]
[122]
Delmore, J.E.; Issa, G.C.; Lemieux, M.E.; Rahl, P.B.; Shi, J.; Jacobs, H.M.; Kastritis, E.; Gilpatrick, T.; Paranal, R.M.; Qi, J.; Chesi, M.; Schinzel, A.C.; McKeown, M.R.; Heffernan, T.P.; Vakoc, C.R.; Bergsagel, P.L.; Ghobrial, I.M.; Richardson, P.G.; Young, R.A.; Hahn, W.C.; Anderson, K.C.; Kung, A.L.; Bradner, J.E.; Mitsiades, C.S. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 2011, 146(6), 904-917.
[http://dx.doi.org/10.1016/j.cell.2011.08.017] [PMID: 21889194]
[123]
Taylor, A.M.; Vaswani, R.G.; Gehling, V.S.; Hewitt, M.C.; Leblanc, Y.; Audia, J.E.; Bellon, S.; Cummings, R.T.; Côté, A.; Harmange, J.C.; Jayaram, H.; Joshi, S.; Lora, J.M.; Mertz, J.A.; Neiss, A.; Pardo, E.; Nasveschuk, C.G.; Poy, F.; Sandy, P.; Setser, J.W.; Sims, R.J., III; Tang, Y.; Albrecht, B.K. Discovery of benzotriazolo[4,3-d][1,4]diazepines as orally active inhibitors of BET bromodomains. ACS Med. Chem. Lett., 2015, 7(2), 145-150.
[http://dx.doi.org/10.1021/ml500411h] [PMID: 26985289]
[124]
Filippakopoulos, P.; Picaud, S.; Fedorov, O.; Keller, M.; Wrobel, M.; Morgenstern, O.; Bracher, F.; Knapp, S. Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg. Med. Chem., 2012, 20(6), 1878-1886.
[http://dx.doi.org/10.1016/j.bmc.2011.10.080] [PMID: 22137933]
[125]
Schmees, N.; Kuhnke, J.; Haendler, B.; Neuhaus, R.; Lejeune, P.; Siegel, S.; Kruger, M.; Fernandez-Montalvan, A.; Kunzer, H.; Gallenkamp, D. BET protein-inhibiting 5-aryl triazole azepines. U.S. Patent 2015299201, 2015.
[126]
Liu, D.; Pratt, J.; Wang, L.; Hasvold, L.A.; Bogdan, A. Bromodomain inhibitors. U.S. Patent 2014256710, 2014.
[127]
Siegel, S.; Bäurle, S.; Cleve, A.; Haendler, B.; Fernández-Montalván, A.; Mönning, U.; Krause, S.; Lejeune, P.; Busemann, M.; Kuhnke, J. Bicyclo 2,3-benzodiazepines and spirocyclically substituted 2,3-benzodiazepines. WO Patent 2014128067, 2014.
[128]
Vadivelu, S.; Rajagopal, S.; Chinnapattu, M.; Gondrala, P.K.; Sivanandhan, D. Tricyclic fused derivatives of 1-(cyclo)alkyl pyridin-2-one useful for the treatment of cancer. WO Patent 2016157221, 2016.
[129]
Kim, Y.H.; Kim, M.; Yoo, M.; Kim, J.E.; Lee, H.K.; Heo, J.N.; Lee, C.O.; Yoo, M.; Jung, K.Y.; Yun, C.S.; Moon, S.W.; Chang, H.K.; Chung, C.W.; Pyo, S.; Choi, S.U.; Park, C.H. A natural compound, aristoyagonine, is identified as a potent bromodomain inhibitor by mid-throughput screening. Biochem. Biophys. Res. Commun., 2018, 503(2), 882-887.
[http://dx.doi.org/10.1016/j.bbrc.2018.06.091] [PMID: 29928885]
[130]
Qin, C.; Hu, Y.; Zhou, B.; Fernandez-Salas, E.; Yang, C.Y.; Liu, L.; McEachern, D.; Przybranowski, S.; Wang, M.; Stuckey, J.; Meagher, J.; Bai, L.; Chen, Z.; Lin, M.; Yang, J.; Ziazadeh, D.N.; Xu, F.; Hu, J.; Xiang, W.; Huang, L.; Li, S.; Wen, B.; Sun, D.; Wang, S. Discovery of QCA570 as an exceptionally potent and efficacious Proteolysis Targeting Chimera (PROTAC) degrader of the bromodomain and Extra-Terminal (BET) proteins capable of inducing complete and durable tumor regression. J. Med. Chem., 2018, 61(15), 6685-6704.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00506] [PMID: 30019901]
[131]
Jiang, F.; Hu, Q.; Zhang, Z.; Li, H.; Li, H.; Zhang, D.; Li, H.; Ma, Y.; Xu, J.; Chen, H.; Cui, Y.; Zhi, Y.; Zhang, Y.; Xu, J.; Zhu, J.; Lu, T.; Chen, Y. Discovery of benzo[cd]indol-2(1H)-ones and pyrrolo[4,3,2-de]quinolin-2(1H)-ones as bromodomain and extra-terminal domain (BET) inhibitors with selectivity for the first bromodomain with potential high efficiency against acute gouty arthritis. J. Med. Chem., 2019, 62(24), 11080-11107.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01010] [PMID: 31789032]
[132]
Blank, J.; Bordas, V.; Cotesta, S.; Guagnano, V.; Rueeger, H.; Vaupel, A. Pyrazolopyrrolidine derivatives and their use in the treatment of disease. U.S. Patent 2014349990, 2014.
[133]
Blank, J.; Bold, G.; Bordas, V.; Cotesta, S.; Guagnano, V.; Rueger, H.; Vaupel, A. Pyrrolopyrrolone derivatives and their use as BET inhibitors. WO Patent 2015075665, 2015.
[134]
Engelhardt, H.; Gianni, D.; Smethurst, C. Substituted [1,2,4]triazolo[4,3-a]pyrazines as BRD4 inhibitors. U.S. Patent 2016129001, 2016.
[135]
Ali, I.; Lee, J.; Go, A.; Choi, G.; Lee, K. Discovery of novel [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment. Bioorg. Med. Chem. Lett., 2017, 27(20), 4606-4613.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.025] [PMID: 28939121]
[136]
Abner, E.; Stoszko, M.; Zeng, L.; Chen, H.C.; Izquierdo-Bouldstridge, A.; Konuma, T.; Zorita, E.; Fanunza, E.; Zhang, Q.; Mahmoudi, T.; Zhou, M.M.; Filion, G.J.; Jordan, A. A new quinoline BRD4 inhibitor targets a distinct latent HIV-1 reservoir for reactivation from other “shock” drugs. J. Virol., 2018, 92(10), e02056-e17.
[http://dx.doi.org/10.1128/JVI.02056-17] [PMID: 29343578]
[137]
Bonazzoli, E.; Predolini, F.; Cocco, E.; Bellone, S.; Altwerger, G.; Menderes, G.; Zammataro, L.; Bianchi, A.; Pettinella, F.; Riccio, F.; Han, C.; Yadav, G.; Lopez, S.; Manzano, A.; Manara, P.; Buza, N.; Hui, P.; Wong, S.; Litkouhi, B.; Ratner, E.; Silasi, D.A.; Huang, G.S.; Azodi, M.; Schwartz, P.E.; Schlessinger, J.; Santin, A.D. Inhibition of BET bromodomain proteins with GS-5829 and GS-626510 in uterine serous carcinoma, a biologically aggressive variant of endometrial cancer. Clin. Cancer Res., 2018, 24(19), 4845-4853.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-0864] [PMID: 29941483]
[138]
Li, C.; Bonazzoli, E.; Bellone, S.; Choi, J.; Dong, W.; Menderes, G.; Altwerger, G.; Han, C.; Manzano, A.; Bianchi, A.; Pettinella, F.; Manara, P.; Lopez, S.; Yadav, G.; Riccio, F.; Zammataro, L.; Zeybek, B.; Yang-Hartwich, Y.; Buza, N.; Hui, P.; Wong, S.; Ravaggi, A.; Bignotti, E.; Romani, C.; Todeschini, P.; Zanotti, L.; Zizioli, V.; Odicino, F.; Pecorelli, S.; Ardighieri, L.; Silasi, D.A.; Litkouhi, B.; Ratner, E.; Azodi, M.; Huang, G.S.; Schwartz, P.E.; Lifton, R.P.; Schlessinger, J.; Santin, A.D. Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors. Proc. Natl. Acad. Sci. USA, 2019, 116(2), 619-624.
[http://dx.doi.org/10.1073/pnas.1814027116] [PMID: 30584090]
[139]
Gilan, O.; Rioja, I.; Knezevic, K.; Bell, M.J.; Yeung, M.M.; Harker, N.R.; Lam, E.Y.N.; Chung, C.W.; Bamborough, P.; Petretich, M.; Urh, M.; Atkinson, S.J.; Bassil, A.K.; Roberts, E.J.; Vassiliadis, D.; Burr, M.L.; Preston, A.G.S.; Wellaway, C.; Werner, T.; Gray, J.R.; Michon, A.M.; Gobbetti, T.; Kumar, V.; Soden, P.E.; Haynes, A.; Vappiani, J.; Tough, D.F.; Taylor, S.; Dawson, S.J.; Bantscheff, M.; Lindon, M.; Drewes, G.; Demont, E.H.; Daniels, D.L.; Grandi, P.; Prinjha, R.K.; Dawson, M.A. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science, 2020, 368(6489), 387-394.
[http://dx.doi.org/10.1126/science.aaz8455] [PMID: 32193360]
[140]
Gosmini, R.; Nguyen, V.L.; Toum, J.; Simon, C.; Brusq, J.M.; Krysa, G.; Mirguet, O.; Riou-Eymard, A.M.; Boursier, E.V.; Trottet, L.; Bamborough, P.; Clark, H.; Chung, C.W.; Cutler, L.; Demont, E.H.; Kaur, R.; Lewis, A.J.; Schilling, M.B.; Soden, P.E.; Taylor, S.; Walker, A.L.; Walker, M.D.; Prinjha, R.K.; Nicodème, E. The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor. J. Med. Chem., 2014, 57(19), 8111-8131.
[http://dx.doi.org/10.1021/jm5010539] [PMID: 25249180]
[141]
Bai, P.; Wey, H.Y.; Patnaik, D.; Lu, X.; Lan, Y.; Rokka, J.; Stephanie, F.; Haggarty, S.J.; Wang, C. Positron emission tomography probes targeting bromodomain and extra-terminal (BET) domains to enable in vivo neuroepigenetic imaging. Chem. Commun. (Camb.), 2019, 55(86), 12932-12935.
[http://dx.doi.org/10.1039/C9CC06734E] [PMID: 31599282]
[142]
Wyce, A.; Ganji, G.; Smitheman, K.N.; Chung, C.W.; Korenchuk, S.; Bai, Y.; Barbash, O.; Le, B.; Craggs, P.D.; McCabe, M.T.; Kennedy-Wilson, K.M.; Sanchez, L.V.; Gosmini, R.L.; Parr, N.; McHugh, C.F.; Dhanak, D.; Prinjha, R.K.; Auger, K.R.; Tummino, P.J. BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PLoS One, 2013, 8(8), e72967.
[http://dx.doi.org/10.1371/journal.pone.0072967] [PMID: 24009722]
[143]
Amans, D.; Atkinson, S.J.; Harrison, L.A.; Hirst, D.J.; Law, R.P.; Lindon, M.; Preston, A.; Seal, J.T.; Wellaway, C.R. 2,3-Disubstituted 1-acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors. WO Patent 2014140076, 2014.
[144]
Bair, K.W.; Herbertz, T.; Kauffman, G.S.; Kayser-Bricker, K.J.; Luke, G.P.; Martin, M.W.; Millan, D.S.; Schiller, S.R. Tetrahy626 droquinoline composition as BET bromodomain inhibitors. WO Patent 2015074064, 2015.
[145]
Yang, S.M.; Urban, D.J.; Yoshioka, M.; Strovel, J.W.; Fletcher, S.; Wang, A.Q.; Xu, X.; Shah, P.; Hu, X.; Hall, M.D.; Jadhav, A.; Maloney, D.J. Discovery and lead identification of quinazoline-based BRD4 inhibitors. Bioorg. Med. Chem. Lett., 2018, 28(21), 3483-3488.
[http://dx.doi.org/10.1016/j.bmcl.2018.08.039] [PMID: 30268702]
[146]
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, P.E.; Knapp, S.; Filippakopoulos, P. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl. Acad. Sci. USA, 2013, 110(49), 19754-19759.
[http://dx.doi.org/10.1073/pnas.1310658110] [PMID: 24248379]
[147]
Bailey, D.; Jahagirdar, R.; Gordon, A.; Hafiane, A.; Campbell, S.; Chatur, S.; Wagner, G.S.; Hansen, H.C.; Chiacchia, F.S.; Johansson, J.; Krimbou, L.; Wong, N.C.; Genest, J. RVX-208: A small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J. Am. Coll. Cardiol., 2010, 55(23), 2580-2589.
[http://dx.doi.org/10.1016/j.jacc.2010.02.035] [PMID: 20513599]
[148]
Sweeney, M.; Nicholls, S.J.; Ray, K.K.; Buhr, K.; Ginsberg, H.; Johansson, J.; Kalantar-Zadeh, K.; Kulikowski, E.; Toth, P.; Wong, N.; Schwartz, G.G. The BET protein inhibitor apabetalone reduces congestive heart failure incidence in patients with acute coronary syndrome and diabetes: Results from the betonmace trial. J. Am. Coll. Cardiol., 2020, 75(11), 168.
[http://dx.doi.org/10.1016/S0735-1097(20)30795-6]
[149]
Fish, P.V.; Filippakopoulos, P.; Bish, G.; Brennan, P.E.; Bunnage, M.E.; Cook, A.S.; Federov, O.; Gerstenberger, B.S.; Jones, H.; Knapp, S.; Marsden, B.; Nocka, K.; Owen, D.R.; Philpott, M.; Picaud, S.; Primiano, M.J.; Ralph, M.J.; Sciammetta, N.; Trzupek, J.D. Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J. Med. Chem., 2012, 55(22), 9831-9837.
[http://dx.doi.org/10.1021/jm3010515] [PMID: 23095041]
[150]
Hu, J.; Wang, Y.; Li, Y.; Cao, D.; Xu, L.; Song, S.; Damaneh, M.S.; Li, J.; Chen, Y.; Wang, X.; Chen, L.; Shen, J.; Miao, Z.; Xiong, B. Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups. Eur. J. Med. Chem., 2018, 150, 156-175.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.070] [PMID: 29525435]
[151]
Hu, J.; Tian, C.Q.; Damaneh, M.S.; Li, Y.; Cao, D.; Lv, K.; Yu, T.; Meng, T.; Chen, D.; Wang, X.; Chen, L.; Li, J.; Song, S.S.; Huan, X.J.; Qin, L.; Shen, J.; Wang, Y.Q.; Miao, Z.H.; Xiong, B. Structure-based discovery and development of a series of potent and selective bromodomain and extra-terminal protein inhibitors. J. Med. Chem., 2019, 62(18), 8642-8663.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01094] [PMID: 31490070]
[152]
McDaniel, K.F.; Wang, L.; Soltwedel, T.; Fidanze, S.D.; Hasvold, L.A.; Liu, D.; Mantei, R.A.; Pratt, J.K.; Sheppard, G.S.; Bui, M.H.; Faivre, E.J.; Huang, X.; Li, L.; Lin, X.; Wang, R.; Warder, S.E.; Wilcox, D.; Albert, D.H.; Magoc, T.J.; Rajaraman, G.; Park, C.H.; Hutchins, C.W.; Shen, J.J.; Edalji, R.P.; Sun, C.C.; Martin, R.; Gao, W.; Wong, S.; Fang, G.; Elmore, S.W.; Shen, Y.; Kati, W.M. Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a potent and orally available bromodomain and extra-terminal domain (BET) family bromodomain inhibitor. J. Med. Chem., 2017, 60(20), 8369-8384.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00746] [PMID: 28949521]
[153]
Zhou, B.; Hu, J.; Xu, F.; Chen, Z.; Bai, L.; Fernandez-Salas, E.; Lin, M.; Liu, L.; Yang, C.Y.; Zhao, Y.; McEachern, D.; Przybranowski, S.; Wen, B.; Sun, D.; Wang, S. Discovery of a small-molecule degrader of bromodomain and extra-terminal (BET) proteins with picomolar cellular potencies and capable of achieving tumor regression. J. Med. Chem., 2018, 61(2), 462-481.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01816] [PMID: 28339196]
[154]
Wellaway, C.R.; Amans, D.; Bamborough, P.; Barnett, H.; Bit, R.A.; Brown, J.A.; Carlson, N.R.; Chung, C.W.; Cooper, A.W.J.; Craggs, P.D.; Davis, R.P.; Dean, T.W.; Evans, J.P.; Gordon, L.; Harada, I.L.; Hirst, D.J.; Humphreys, P.G.; Jones, K.L.; Lewis, A.J.; Lindon, M.J.; Lugo, D.; Mahmood, M.; McCleary, S.; Medeiros, P.; Mitchell, D.J.; O’Sullivan, M.; Le Gall, A.; Patel, V.K.; Patten, C.; Poole, D.L.; Shah, R.R.; Smith, J.E.; Stafford, K.A.J.; Thomas, P.J.; Vimal, M.; Wall, I.D.; Watson, R.J.; Wellaway, N.; Yao, G.; Prinjha, R.K. Discovery of a bromodomain and extraterminal inhibitor with a low predicted human dose through synergistic use of encoded library technology and fragment screening. J. Med. Chem., 2020, 63(2), 714-746.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01670] [PMID: 31904959]
[155]
Mu, X.; Bai, L.; Xu, Y.; Wang, J.; Lu, H. Protein targeting chimeric molecules specific for dual bromodomain 4 (BRD4) and Polo-like kinase 1 (PLK1) proteins in acute myeloid leukemia cells. Biochem. Biophys. Res. Commun., 2020, 521(4), 833-839.
[http://dx.doi.org/10.1016/j.bbrc.2019.11.007] [PMID: 31708096]
[156]
Bai, L.; Zhou, B.; Yang, C.Y.; Ji, J.; McEachern, D.; Przybranowski, S.; Jiang, H.; Hu, J.; Xu, F.; Zhao, Y.; Liu, L.; Fernandez-Salas, E.; Xu, J.; Dou, Y.; Wen, B.; Sun, D.; Meagher, J.; Stuckey, J.; Hayes, D.F.; Li, S.; Ellis, M.J.; Wang, S. Targeted degradation of BET proteins in triple-negative breast cancer. Cancer Res., 2017, 77(9), 2476-2487.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2622] [PMID: 28209615]
[157]
Wang, L.; Pratt, J.K.; Soltwedel, T.; Sheppard, G.S.; Fidanze, S.D.; Liu, D.; Hasvold, L.A.; Mantei, R.A.; Holms, J.H.; McClellan, W.J.; Wendt, M.D.; Wada, C.; Frey, R.; Hansen, T.M.; Hubbard, R.; Park, C.H.; Li, L.; Magoc, T.J.; Albert, D.H.; Lin, X.; Warder, S.E.; Kovar, P.; Huang, X.; Wilcox, D.; Wang, R.; Rajaraman, G.; Petros, A.M.; Hutchins, C.W.; Panchal, S.C.; Sun, C.; Elmore, S.W.; Shen, Y.; Kati, W.M.; McDaniel, K.F. Fragment-based, structure-enabled discovery of novel pyridones and pyridone macrocycles as potent bromodomain and extra-terminal domain (BET) family bromodomain inhibitors. J. Med. Chem., 2017, 60(9), 3828-3850.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00017] [PMID: 28368119]
[158]
Yoo, M.; Yoo, M.; Kim, J.E.; Lee, H.K.; Lee, C.O.; Park, C.H.; Jung, K.Y. Synthesis and biological evaluation of indazole-4,7-dione derivatives as novel BRD4 inhibitors. Arch. Pharm. Res., 2018, 41(1), 46-56.
[http://dx.doi.org/10.1007/s12272-017-0978-y] [PMID: 29103140]
[159]
Bamborough, P.; Diallo, H.; Goodacre, J.D.; Gordon, L.; Lewis, A.; Seal, J.T.; Wilson, D.M.; Woodrow, M.D.; Chung, C.W. Fragment-based discovery of bromodomain inhibitors part 2: Optimization of phenylisoxazole sulfonamides. J. Med. Chem., 2012, 55(2), 587-596.
[http://dx.doi.org/10.1021/jm201283q] [PMID: 22136469]
[160]
Hewings, D.S.; Fedorov, O.; Filippakopoulos, P.; Martin, S.; Picaud, S.; Tumber, A.; Wells, C.; Olcina, M.M.; Freeman, K.; Gill, A.; Ritchie, A.J.; Sheppard, D.W.; Russell, A.J.; Hammond, E.M.; Knapp, S.; Brennan, P.E.; Conway, S.J. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J. Med. Chem., 2013, 56(8), 3217-3227.
[http://dx.doi.org/10.1021/jm301588r] [PMID: 23517011]
[161]
Hewings, D.S.; Wang, M.; Philpott, M.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Vuppusetty, C.; Marsden, B.; Knapp, S.; Conway, S.J.; Heightman, T.D. 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J. Med. Chem., 2011, 54(19), 6761-6770.
[http://dx.doi.org/10.1021/jm200640v] [PMID: 21851057]
[162]
Ren, B.; Zhou, C.; Wang, H. Substituted 5-(3,5-dimethylisoxazole-4-yl) indoline-2-ones. WO Patent 2014173241, 2014.
[163]
Aktoudianakis, E.; Chin, G.; Corkey, B.K.; Du, J.; Elbel, K.; Jiang, R.H.; Kobayashi, T.; Martinez, R.; Metobo, S.; Mish, M.; Shevick, S.; Sperandio, D.; Yang, H.; Zablocki, J. Benzimidazolone derivatives as bromodomain inhibitors. WO Patent 2014160873, 2014.
[164]
Engelhardt, H.; Gianni, D.; Mantoulidis, A.; Smethurst, C. Indolinone analogues as BRD4 inhibitors. WO Patent 2014154760, 2014.
[165]
Mirguet, O.; Lamotte, Y.; Donche, F.; Toum, J.; Gellibert, F.; Bouillot, A.; Gosmini, R.; Nguyen, V.L.; Delannée, D.; Seal, J.; Blandel, F.; Boullay, A.B.; Boursier, E.; Martin, S.; Brusq, J.M.; Krysa, G.; Riou, A.; Tellier, R.; Costaz, A.; Huet, P.; Dudit, Y.; Trottet, L.; Kirilovsky, J.; Nicodeme, E. From ApoA1 upregulation to BET family bromodomain inhibition: Discovery of I-BET151. Bioorg. Med. Chem. Lett., 2012, 22(8), 2963-2967.
[http://dx.doi.org/10.1016/j.bmcl.2012.01.125] [PMID: 22386529]
[166]
Ran, X.; Zhao, Y.; Liu, L.; Bai, L.; Yang, C.Y.; Zhou, B.; Meagher, J.L.; Chinnaswamy, K.; Stuckey, J.A.; Wang, S. Structure-based design of gamma-carboline analogues as potent and specific BET bromodomain inhibitors. J. Med. Chem., 2015, 58(12), 4927-4939.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00613] [PMID: 26080064]
[167]
Slassi, A.; Dove, P. Fluorinated imidazo[4,5-c]quinoline derivatives as inhibitors of bromodomain containing proteins. WO Patent 2016123709, 2016.
[168]
Zhao, Y.; Zhou, B.; Bai, L.; Liu, L.; Yang, C.Y.; Meagher, J.L.; Stuckey, J.A.; McEachern, D.; Przybranowski, S.; Wang, M.; Ran, X.; Aguilar, A.; Hu, Y.; Kampf, J.W.; Li, X.; Zhao, T.; Li, S.; Wen, B.; Sun, D.; Wang, S. Structure-based discovery of CF53 as a potent and orally bioavailable bromodomain and extra-terminal (BET) bromodomain inhibitor. J. Med. Chem., 2018, 61(14), 6110-6120.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00483] [PMID: 30015487]

Rights & Permissions Print Cite
Article Metrics
46
4
World Chagas Disease
© 2024 Bentham Science Publishers | Privacy Policy