Bromodomain and Extra-Terminal Motif Inhibitors: a Review of Preclinical and Clinical Advances in Cancer Therapy

References

• Choudhary C, Kumar C, Gnad F et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325(5942), 834–840 (2009).
   PubMed Web of Science ®Google Scholar
• Kuo MH, Allis CD. Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 20(8), 615–626 (1998).
   PubMed Web of Science ®Google Scholar
• Lombardi PM, Cole KE, Dowling DP, Christianson DW. Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes. Curr. Opin. Struct. Biol. 21(6), 735–743 (2011).
   PubMed Web of Science ®Google Scholar
• Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat. Rev. Drug Discov. 13(5), 337–356 (2014).
   PubMed Web of Science ®Google Scholar
• Barneda-Zahonero B, Parra M. Histone deacetylases and cancer. Mol. Oncol. 6(6), 579–589 (2012).
   PubMed Web of Science ®Google Scholar
• Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399(6735), 491–496 (1999).
   PubMed Web of Science ®Google Scholar
• Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6(4), a018713 (2014).
   PubMed Web of Science ®Google Scholar
• Chen Y, Fu LL, Wen X et al. Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis. 5, e1047 (2014).
   PubMed Web of Science ®Google Scholar
• Anand P, Brown JD, Lin CY et al. BET bromodomains mediate transcriptional pause release in heart failure. Cell 154(3), 569–582 (2013).
   PubMed Web of Science ®Google Scholar
• Sanchez R, Meslamani J, Zhou MM. The bromodomain: from epigenome reader to druggable target. Biochim. Biophys. Acta 1839(8), 676–685 (2014).
   PubMed Web of Science ®Google Scholar
• Barbieri I, Cannizzaro E, Dawson MA. Bromodomains as therapeutic targets in cancer. Brief. Funct. Genomics 12(3), 219–230 (2013).
   PubMed Web of Science ®Google Scholar
• Zhang G, Sanchez R, Zhou MM. Scaling the druggability landscape of human bromodomains, a new class of drug targets. J. Med. Chem. 55(17), 7342–7345 (2012).
   PubMed Web of Science ®Google Scholar
• Loven J, Hoke HA, Lin CY et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153(2), 320–334 (2013).
   PubMed Web of Science ®Google Scholar
• Filippakopoulos P, Qi J, Picaud S et al. Selective inhibition of BET bromodomains. Nature 468(7327), 1067–1073 (2010).
   PubMed Web of Science ®Google Scholar
• Fu LL, Tian M, Li X et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget 6(8), 5501–5516 (2015).
   PubMed Web of Science ®Google Scholar
• Houzelstein D, Bullock SL, Lynch DE, Grigorieva EF, Wilson VA, Beddington RS. Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4. Mol. Cell. Biol. 22(11), 3794–3802 (2002).
   PubMed Web of Science ®Google Scholar
• Devaiah BN, Singer DS. Cross-talk among RNA polymerase II kinases modulates C-terminal domain phosphorylation. J. Biol. Chem. 287(46), 38755–38766 (2012).
   PubMed Web of Science ®Google Scholar
• Rahman S, Sowa ME, Ottinger M et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol. Cell. Biol. 31(13), 2641–2652 (2011).
   PubMed Web of Science ®Google Scholar
• Vollmuth F, Blankenfeldt W, Geyer M. Structures of the dual bromodomains of the P-TEFb-activating protein Brd4 at atomic resolution. J. Biol. Chem. 284(52), 36547–36556 (2009).
   PubMed Web of Science ®Google Scholar
• Devaiah BN, Singer DS. Two faces of Brd4: mitotic bookmark and transcriptional lynchpin. Transcription 4(1), 13–17 (2013).
   PubMedGoogle Scholar
• Zhao R, Nakamura T, Fu Y, Lazar Z, Spector DL. Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activation. Nat. Cell Biol. 13(11), 1295–1304 (2011).
   PubMed Web of Science ®Google Scholar
• Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nat. Rev. Cancer 12(7), 465–477 (2012).
   PubMed Web of Science ®Google Scholar
• Herait PE, Berthon C, Thieblemont C et al. Abstract CT231: BET-bromodomain inhibitor OTX015 shows clinically meaningful activity at nontoxic doses: interim results of an ongoing Phase I trial in hematologic malignancies. Cancer Res. 74(19 Suppl.), CT231–CT231 (2014).
   Web of Science ®Google Scholar
• Stewart HJ, Horne GA, Bastow S, Chevassut TJ. BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1. Cancer Med. 2(6), 826–835 (2013).
   PubMed Web of Science ®Google Scholar
• Dawson MA, Prinjha RK, Dittmann A et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478(7370), 529–533 (2011).
   PubMed Web of Science ®Google Scholar
• Zuber J, Shi J, Wang E et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478(7370), 524–528 (2011).
   PubMed Web of Science ®Google Scholar
• Mertz JA, Conery AR, Bryant BM et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108(40), 16669–16674 (2011).
   PubMed Web of Science ®Google Scholar
• Ott CJ, Kopp N, Bird L et al. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood 120(14), 2843–2852 (2012).
   PubMed Web of Science ®Google Scholar
• Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin. Cancer Biol. 16(4), 318–330 (2006).
   PubMed Web of Science ®Google Scholar
• Feng Q, Zhang Z, Shea MJ et al. An epigenomic approach to therapy for tamoxifen-resistant breast cancer. Cell Res. 24(7), 809–819 (2014).
   PubMed Web of Science ®Google Scholar
• Chen H, Liu H, Qing G. Targeting oncogenic Myc as a strategy for cancer treatment. Signal. Transduct. Target Ther. 3, 5 (2018).
   PubMed Web of Science ®Google Scholar
• Pastori C, Daniel M, Penas C et al. BET bromodomain proteins are required for glioblastoma cell proliferation. Epigenetics 9(4), 611–620 (2014).
   PubMed Web of Science ®Google Scholar
• Klein K, Kabala PA, Grabiec AM et al. The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis. 75(2), 422–429 (2016).
   PubMed Web of Science ®Google Scholar
• Muller S, Filippakopoulos P, Knapp S. Bromodomains as therapeutic targets. Expert Rev. Mol. Med. 13, e29 (2011).
   PubMed Web of Science ®Google Scholar
• Grayson AR, Walsh EM, Cameron MJ et al. MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene 33(13), 1736–1742 (2014).
   PubMed Web of Science ®Google Scholar
• Sachchidanand, Resnick-Silverman L, Yan S et al. Target structure-based discovery of small molecules that block human p53 and CREB binding protein association. Chem. Biol. 13(1), 81–90 (2006).
   PubMedGoogle Scholar
• Borah JC, Mujtaba S, Karakikes I et al. A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes. Chem. Biol. 18(4), 531–541 (2011).
   PubMedGoogle Scholar
• Ceribelli M, Kelly PN, Shaffer AL et al. Blockade of oncogenic IkappaB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors. Proc. Natl Acad. Sci. USA 111(31), 11365–11370 (2014).
   PubMed Web of Science ®Google Scholar
• Picaud S, Da Costa D, Thanasopoulou A et al. PFI-1, a highly selective protein interaction inhibitor, targeting BET bromodomains. Cancer Res. 73(11), 3336–3346 (2013).
   PubMed Web of Science ®Google Scholar
• Beesley AH, Stirnweiss A, Ferrari E et al. Comparative drug screening in NUT midline carcinoma. Br. J. Cancer 110(5), 1189–1198 (2014).
   PubMed Web of Science ®Google Scholar
• Beroukhim R, Mermel CH, Porter D et al. The landscape of somatic copy-number alteration across human cancers. Nature 463(7283), 899–905 (2010).
   PubMed Web of Science ®Google Scholar
• Jain M, Arvanitis C, Chu K et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297(5578), 102–104 (2002).
   PubMed Web of Science ®Google Scholar
• Soucek L, Helmer-Citterich M, Sacco A, Jucker R, Cesareni G, Nasi S. Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene 17(19), 2463–2472 (1998).
   PubMed Web of Science ®Google Scholar
• Soucek L, Jucker R, Panacchia L, Ricordy R, Tato F, Nasi S. Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. Cancer Res. 62(12), 3507–3510 (2002).
   PubMed Web of Science ®Google Scholar
• Vervoorts J, Luscher-Firzlaff JM, Rottmann S et al. Stimulation of c-MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. Embo. Rep. 4(5), 484–490 (2003).
   PubMed Web of Science ®Google Scholar
• Frank SR, Parisi T, Taubert S et al. MYC recruits the TIP60 histone acetyltransferase complex to chromatin. Embo. Rep. 4(6), 575–580 (2003).
   PubMed Web of Science ®Google Scholar
• Shou Y, Martelli ML, Gabrea A et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc. Natl Acad. Sci. USA 97(1), 228–233 (2000).
   PubMed Web of Science ®Google Scholar
• Delmore JE, Issa GC, Lemieux ME et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146(6), 904–917 (2011).
   PubMed Web of Science ®Google Scholar
• Loosveld M, Castellano R, Gon S et al. Therapeutic targeting of c-Myc in T-cell acute lymphoblastic leukemia, T-ALL. Oncotarget 5(10), 3168–3172 (2014).
   PubMedGoogle Scholar
• Fiskus W, Sharma S, Qi J et al. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD. Mol. Cancer Ther. 13(10), 2315–2327 (2014).
   PubMed Web of Science ®Google Scholar
• Liu S, Walker SR, Nelson EA et al. Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2. Mol. Cancer Ther. 13(5), 1194–1205 (2014).
   PubMed Web of Science ®Google Scholar
• Hogg SJ, Vervoort SJ, Deswal S et al. BET-bromodomain inhibitors engage the host immune system and regulate expression of the immune checkpoint ligand PD-L1. Cell Rep. 18(9), 2162–2174 (2017).
   PubMed Web of Science ®Google Scholar
• Henssen A, Thor T, Odersky A et al. BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget 4(11), 2080–2095 (2013).
   PubMedGoogle Scholar
• Venkataraman S, Alimova I, Balakrishnan I et al. Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget 5(9), 2355–2371 (2014).
   PubMedGoogle Scholar
• Bandopadhayay P, Bergthold G, Nguyen B et al. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin. Cancer Res. 20(4), 912–925 (2014).
   PubMed Web of Science ®Google Scholar
• Cheng Z, Gong Y, Ma Y et al. Inhibition of BET bromodomain targets genetically diverse glioblastoma. Clin. Cancer Res. 19(7), 1748–1759 (2013).
   PubMed Web of Science ®Google Scholar
• Taylor IC, Hutt-Cabezas M, Brandt WD et al. Disrupting NOTCH slows diffuse intrinsic pontine glioma growth, enhances radiation sensitivity, and shows combinatorial efficacy with bromodomain inhibition. J. Neuropathol. Exp. Neurol. 74(8), 778–790 (2015).
   PubMed Web of Science ®Google Scholar
• Suzuki H, Gabrielson E, Chen W et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat. Genet. 31(2), 141–149 (2002).
   PubMed Web of Science ®Google Scholar
• Vedeld HM, Merok M, Jeanmougin M et al. CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers. Int. J. Cancer 141(5), 967–976 (2017).
   PubMed Web of Science ®Google Scholar
• Xiang JF, Yin QF, Chen T et al. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 24(5), 513–531 (2014).
   PubMed Web of Science ®Google Scholar
• Mccleland ML, Mesh K, Lorenzana E et al. CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J. Clin. Invest. 126(2), 639–652 (2016).
   PubMed Web of Science ®Google Scholar
• Zhang Y, Tian S, Xiong J, Zhou Y, Song H, Liu C. JQ-1 inhibits colon cancer proliferation via suppressing Wnt/β-catenin signaling and miR-21. Chem. Res. Toxicol. 31(5), 302–307 (2018).
   PubMed Web of Science ®Google Scholar
• Bihani T, Ezell SA, Ladd B et al. Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers. Oncotarget 6(4), 2407–2420 (2015).
   PubMedGoogle Scholar
• Borbely G, Haldosen LA, Dahlman-Wright K, Zhao C. Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells. Oncotarget 6(32), 33623–33635 (2015).
   PubMed Web of Science ®Google Scholar
• Nieto-Jimenez C, Alcaraz-Sanabria A, Perez-Pena J et al. Targeting basal-like breast tumors with bromodomain and extraterminal domain (BET) and polo-like kinase inhibitors. Oncotarget 8(12), 19478–19490 (2017).
   PubMedGoogle Scholar
• Vazquez R, Riveiro ME, Astorgues-Xerri L et al. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget 8(5), 7598–7613 (2017).
   PubMedGoogle Scholar
• Perez-Salvia M, Simo-Riudalbas L, Llinas-Arias P et al. Bromodomain inhibition shows antitumoral activity in mice and human luminal breast cancer. Oncotarget 8(31), 51621–51629 (2017).
   PubMedGoogle Scholar
• Stuhlmiller TJ, Miller SM, Zawistowski JS et al. Inhibition of lapatinib-induced kinome reprogramming in ERBB2-positive breast cancer by targeting BET family bromodomains. Cell Rep. 11(3), 390–404 (2015).
   PubMed Web of Science ®Google Scholar
• Andrieu G, Belkina AC, Denis GV. Clinical trials for BET inhibitors run ahead of the science. Drug Discov. Today Technol. 19, 45–50 (2016).
   PubMedGoogle Scholar
• Coude MM, Braun T, Berrou J et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget 6(19), 17698–17712 (2015).
   PubMedGoogle Scholar
• Boi M, Gaudio E, Bonetti P 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(7), 1628–1638 (2015).
   PubMed Web of Science ®Google Scholar
• Bai L, Zhou B, Yang CY et al. Targeted degradation of BET proteins in triple-negative breast cancer. Cancer Res. 77(9), 2476–2487 (2017).
   PubMed Web of Science ®Google Scholar
• Bui MH, Lin X, Albert DH et al. Preclinical characterization of BET family bromodomain inhibitor ABBV-075 suggests combination therapeutic strategies. Cancer Res. 77(11), 2976–2989 (2017).
   PubMed Web of Science ®Google Scholar
• Long J, Li B, Rodriguez-Blanco J et al. The BET bromodomain inhibitor I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers. J. Biol. Chem. 289(51), 35494–35502 (2014).
   PubMed Web of Science ®Google Scholar
• Chaidos A, Caputo V, Gouvedenou K et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 123(5), 697–705 (2014).
   PubMed Web of Science ®Google Scholar
• Dawson MA, Gudgin EJ, Horton SJ et al. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia 28(2), 311–320 (2014).
   PubMed Web of Science ®Google Scholar
• Garnier JM, Sharp PP, Burns CJ. BET bromodomain inhibitors: a patent review. Expert Opin. Ther. Pat. 24(2), 185–199 (2014).
   PubMed Web of Science ®Google Scholar
• Wyce A, Degenhardt Y, Bai Y et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 4(12), 2419–2429 (2013).
   PubMed Web of Science ®Google Scholar
• Wyce A, Ganji G, Smitheman KN et al. BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PLoS ONE 8(8), e72967 (2013).
   PubMed Web of Science ®Google Scholar
• Moros A, Rodriguez V, Saborit-Villarroya I et al. Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma. Leukemia 28(10), 2049–2059 (2014).
   PubMed Web of Science ®Google Scholar
• Diaz T, Rodriguez V, Lozano E et al. The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling. Haematologica 102(10), 1776–1784 (2017).
   PubMed Web of Science ®Google Scholar
• De Paula Careta F, Gobessi S, Panepucci RA et al. The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets. Haematologica 97(8), 1246–1254 (2012).
   PubMed Web of Science ®Google Scholar
• Thorsteinsdottir U, Mamo A, Kroon E et al. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood 99(1), 121–129 (2002).
   PubMed Web of Science ®Google Scholar
• Picaud S, Wells C, Felletar I et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl Acad. Sci. USA 110(49), 19754–19759 (2013).
   PubMed Web of Science ®Google Scholar
• Kempen HJ, Bellus D, Fedorov O et al. Stimulation of hepatic apolipoprotein A-I production by novel thieno-triazolodiazepines: roles of the classical benzodiazepine receptor, PAF receptor, and bromodomain binding. Lipid Insights 6, 47–54 (2013).
   PubMedGoogle Scholar
• Fabre C, Gobbi M, Ezzili C et al. Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients. Cancer Chemother. Pharmacol. 74(5), 1057–1064 (2014).
   PubMed Web of Science ®Google Scholar
• Martin MP, Olesen SH, Georg GI, Schonbrunn E. Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. ACS Chem. Biol. 8(11), 2360–2365 (2013).
   PubMed Web of Science ®Google Scholar
• Massard C, Soria JC, Stathis A et al. A Phase Ib trial with MK-8628/OTX015, a small molecule inhibitor of bromodomain (BRD) and extra-terminal (BET) proteins, in patients with selected advanced solid tumors. Eur. J. Cancer 69, S2–S3 (2016).
   Web of Science ®Google Scholar
• Postel-Vinay S, Herbschleb K, Massard C et al. First-in-human Phase I dose escalation study of the Bromodomain and Extra-Terminal motif (BET) inhibitor BAY 1238097 in subjects with advanced malignancies. Eur. J. Cancer 69, S7–S8 (2016).
   Web of Science ®Google Scholar
• Stathis A, Zucca E, Bekradda M et al. Clinical response of carcinomas harboring the BRD4-NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628. Cancer Discov. 6(5), 492–500 (2016).
   PubMed Web of Science ®Google Scholar
• Bernasconi E, Gaudio E, Lejeune P et al. Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma. Br. J. Haematol. 178(6), 936–948 (2017).
   PubMed Web of Science ®Google Scholar
• Borthakur G, Wolff J, Aldoss I et al. First-In-Human Study of ABBV-075 (Mivebresib), a pan-inhibitor of bromodomain and extra terminal (BET) proteins, in patients (Pts) with relapsed/refractory (RR) acute myeloid leukemia (AML): preliminary data. Clin. Lymphoma, Myeloma Leuk. 18, S203 (2018).
   Web of Science ®Google Scholar
• Stratikopoulos EE, Dendy M, Szabolcs M et al. Kinase and BET inhibitors together clamp inhibition of PI3K signaling and overcome resistance to therapy. Cancer Cell 27(6), 837–851 (2015).
   PubMed Web of Science ®Google Scholar
• Tontsch-Grunt U, Savarese F, Baum A et al. Combination of the novel BET inhibitor BI 894999 with CDK9 inhibition suggests a promising regimen for the treatment of AML. Eur. J. Cancer 69, S89 (2016).
   Web of Science ®Google Scholar
• Bolin S, Borgenvik A, Persson C et al. Abstract 2473: combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. Cancer Res. 76(14 Suppl.), 2473–2473 (2016).
   Google Scholar
• Muralidharan SV, Bhadury J, Nilsson LM, Green LC, Mclure KG, Nilsson JA. BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells. Oncogene 35(36), 4689–4697 (2016).
   PubMed Web of Science ®Google Scholar
• Peirs S, Frismantas V, Matthijssens F et al. Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia. Leukemia 31(10), 2037–2047 (2017).
   PubMed Web of Science ®Google Scholar
• Sarker D, Ang JE, Baird R et al. First-in-human Phase I study of pictilisib (GDC-0941), a potent pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. 21(1), 77–86 (2015).
   Google Scholar
• Bauer K, Berger D, Zielinski CC, Valent P, Grunt TW. Hitting two oncogenic machineries in cancer cells: cooperative effects of the multi-kinase inhibitor ponatinib and the BET bromodomain blockers JQ1 or dBET1 on human carcinoma cells. Oncotarget 9(41), 26491–26506 (2018).
   PubMedGoogle Scholar
• Jang JE, Eom JI, Jeung HK et al. Targeting AMPK-ULK1-mediated autophagy for combating BET inhibitor resistance in acute myeloid leukemia stem cells. Autophagy 13(4), 761–762 (2017).
   PubMed Web of Science ®Google Scholar
• Jang JE, Eom JI, Jeung HK et al. AMPK-ULK1-mediated autophagy confers resistance to BET inhibitor JQ1 in acute myeloid leukemia stem cells. Clin. Cancer Res. 23(11), 2781–2794 (2017).
   PubMed Web of Science ®Google Scholar
• Wu T, Wang G, Chen W et al. Co-inhibition of BET proteins and NF-kappaB as a potential therapy for colorectal cancer through synergistic inhibiting MYC and FOXM1 expressions. Cell Death Dis. 9(3), 315 (2018).
   PubMedGoogle Scholar
• Ling YH, Liebes L, Ng B et al. PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol. Cancer Ther. 1(10), 841–849 (2002).
   PubMed Web of Science ®Google Scholar
• Rathert P, Roth M, Neumann T et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525(7570), 543–547 (2015).
   PubMed Web of Science ®Google Scholar
• Kumar K, Raza SS, Knab LM et al. GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1. Sci. Rep. 5, 9489 (2015).
   PubMed Web of Science ®Google Scholar
• Shu S, Lin CY, He HH et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529(7586), 413–417 (2016).
   PubMed Web of Science ®Google Scholar
• Lucas X, Wohlwend D, Hugle M et al. 4-Acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew. Chem. Int. Ed. Engl. 52(52), 14055–14059 (2013).
   PubMed Web of Science ®Google Scholar
• Bolden JE, Tasdemir N, Dow LE et al. Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. Cell Rep. 8(6), 1919–1929 (2014).
   PubMed Web of Science ®Google Scholar
• Aftimos PG, Bechter O, Awada A et al. Phase I first-in-man trial of a novel bromodomain and extra-terminal domain (BET) inhibitor (BI 894999) in patients (Pts) with advanced solid tumors. J. Clin. Oncol. 35(15 Suppl.), 2504–2504 (2017).
   Google Scholar
• Blum KA, Abramson J, Maris M et al. 41OA Phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma. Ann. Oncol. 29(Suppl. 3), mdy048–mdy048 (2018).
   Google Scholar
• Hottinger AF, Sanson M, Moyal E et al. Dose optimization of MK-8628 (OTX015), a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins, in patients (pts) with recurrent glioblastoma (GB). J. Clin. Oncol. 34(15 Suppl.), e14123–e14123 (2016).
   Web of Science ®Google Scholar
• Berthon C, Raffoux E, Thomas X et al. Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, Phase 1 study. Lancet Haematol. 3(4), e186–e195 (2016).
   PubMed Web of Science ®Google Scholar
• Amorim S, Stathis A, Gleeson M et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, Phase 1 study. Lancet Haematol. 3(4), e196–e204 (2016).
   PubMed Web of Science ®Google Scholar
• Patnaik A, Carvajal RD, Komatsubara KM et al. Phase Ib/2a study of PLX51107, a small molecule BET inhibitor, in subjects with advanced hematological malignancies and solid tumors. J. Clin. Oncol. 36(15 Suppl.), 2550–2550 (2018).
   Web of Science ®Google Scholar
• Bradner JE, Hnisz D, Young RA. Transcriptional addiction in cancer. Cell 168(4), 629–643 (2017).
   PubMed Web of Science ®Google Scholar