Dual‐target inhibitors of bromodomain and extra‐terminal proteins in cancer: A review from medicinal chemistry perspectives

Selective inhibition of BET bromodomains

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BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc

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The PI3K Pathway in Human Disease

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Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation

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Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer

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RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

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Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family

Filippakopoulos, P., Picaud, S., Mangos, M., Keates, T., Lambert, J., Baršytė-Lovejoy, D., Felletár, I., Volkmer, R., Müller, S., Pawson, T. J., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.013 · Cited by 1,719 · see citing works

Suppression of inflammation by a synthetic histone mimic

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Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia

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Identification of ALK as a major familial neuroblastoma predisposition gene

Mossé, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., et al. (2008) · Nature · doi:10.1038/nature07261 · Cited by 1,407 · see citing works

Epigenetic protein families: a new frontier for drug discovery

Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K., & Schapira, M. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3674 · Cited by 1,327 · see citing works

The Bromodomain Protein Brd4 Is a Positive Regulatory Component of P-TEFb and Stimulates RNA Polymerase II-Dependent Transcription

Jang, M. K., Mochizuki, K., Zhou, M., Jeong, H., Brady, J. N., & Ozato, K. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.06.027 · Cited by 1,301 · see citing works

c-Myc Regulates Transcriptional Pause Release

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Targeting bromodomains: epigenetic readers of lysine acetylation

Filippakopoulos, P., & Knapp, S. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4286 · Cited by 1,274 · see citing works

The General Transcription Machinery and General Cofactors

Thomas, M. C., & Chiang, C. (2006) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409230600648736 · Cited by 923 · see citing works

Targeting transcription factors in cancer — from undruggable to reality

Bushweller, J. H. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0196-7 · Cited by 919 · see citing works

The Mechanisms behind the Therapeutic Activity of BET Bromodomain Inhibition

Shi, J., & Vakoc, C. R. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.016 · Cited by 881 · see citing works

BET domain co-regulators in obesity, inflammation and cancer

Belkina, A. C., & Denis, G. V. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3256 · Cited by 727 · see citing works

BRD4 and Cancer: going beyond transcriptional regulation

Donati, B., Lorenzini, E., & Ciarrocchi, A. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0915-9 · Cited by 713 · see citing works

The Double Bromodomain-containing Chromatin Adaptor Brd4 and Transcriptional Regulation

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Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition

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Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Shu, S., Lin, C. Y., He, H. H., Witwicki, R. M., Tabassum, D. P., Roberts, J. M., Janiszewska, M., Jin Huh, S., Liang, Y., Ryan, J., et al. (2016) · Nature · doi:10.1038/nature16508 · Cited by 632 · see citing works

Protein Lysine Acetylation by p300/CBP

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Brd4 Coactivates Transcriptional Activation of NF-κB via Specific Binding to Acetylated RelA

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Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor

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BET inhibitor resistance emerges from leukaemia stem cells

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Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

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RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain

Picaud, S., Wells, C. D., Felletár, I., Brotherton, D. H., Martin, S., Savitsky, P. A., Díez-Dacal, B., Philpott, M., Bountra, C., Lingard, H., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1310658110 · Cited by 489 · see citing works

PLK1, A Potential Target for Cancer Therapy

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PI3K signaling in cancer: beyond AKT

Lien, E. C., Dibble, C. C., & Toker, A. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.02.007 · Cited by 446 · see citing works

Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation

Gilan, O., Rioja, I., Knezevic, K., Bell, M. J., Yeung, M. M., Harker, N., Lam, E. Y. N., Chung, C., Bamborough, P., Petretich, M., et al. (2020) · Science · doi:10.1126/science.aaz8455 · Cited by 446 · see citing works

BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression

Zhu, H., Bengsch, F., Svoronos, N., Rutkowski, M. R., Bitler, B. G., Allegrezza, M. J., Yokoyama, Y., Kossenkov, A. V., Bradner, J. E., Conejo-Garcia, J. R., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.032 · Cited by 435 · see citing works

Synthetic lethal therapies for cancer: what’s next after PARP inhibitors?

Ashworth, A., & Lord, C. J. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0055-6 · Cited by 420 · see citing works

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer

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., et al. (2020) · Nature · doi:10.1038/s41586-020-1930-8 · Cited by 408 · see citing works

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Gutteridge, R. E. A., Ndiaye, M. A., Liu, X., & Ahmad, N. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0897 · Cited by 406 · see citing works

BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain

Devaiah, B. N., Lewis, B. A., Cherman, N., Hewitt, M. C., Albrecht, B. K., Robey, P. G., Ozato, K., Sims, R. J., & Singer, D. S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1120422109 · Cited by 379 · see citing works

BET inhibitors: a novel epigenetic approach

Doroshow, D. B., Eder, J. P., & LoRusso, P. M. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx157 · Cited by 378 · see citing works

BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin

Devaiah, B. N., Case‐Borden, C., Gégonne, A., Hsu, C. H., Chen, Q., Meerzaman, D. M., Dey, A., Ozato, K., & Singer, D. S. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3228 · Cited by 364 · see citing works

The structure of P‐TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation

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Discovery of 5-[[4-[(2,3-Dimethyl-2 H -indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor

Harris, P. A., Boloor, A., Cheung, M., Kumar, R., Crosby, R. M., Davis‐Ward, R. G., Epperly, A. H., Hinkle, K. W., Hunter, R., Johnson, J. H., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800566m · Cited by 356 · see citing works

The role of the ALK receptor in cancer biology.

Hallberg, B., & Palmer, R. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw301 · Cited by 356 · see citing works

Phospho Switch Triggers Brd4 Chromatin Binding and Activator Recruitment for Gene-Specific Targeting

Wu, S.-Y., Lee, A.-Y., Lai, H., Zhang, H., & Chiang, C. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.12.006 · Cited by 350 · see citing works

Dual kinase-bromodomain inhibitors for rationally designed polypharmacology

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Prostate cancer–associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4

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Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains

Chung, C., Coste, H., White, J. H. M., Mirguet, O., Wilde, J. I., Gosmini, R. L., Delves, C. J., Magny, S. D., Woodward, R., Hughes, S. A., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm200108t · Cited by 334 · see citing works

The ALKF1174L Mutation Potentiates the Oncogenic Activity of MYCN in Neuroblastoma

Berry, T., Luther, W., Bhatnagar, N., Jamin, Y., Poon, E., Sanda, T., Pei, D., Sharma, B., Vetharoy, W., Hallsworth, A., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.06.001 · Cited by 325 · see citing works

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling

Floyd, S., 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., et al. (2013) · Nature · doi:10.1038/nature12147 · Cited by 324 · see citing works

BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1

Hogg, S. J., Vervoort, S. J., Deswal, S., Ott, C. J., Li, J., Cluse, L. A., Beavis, P. A., Darcy, P. K., Martin, B. P., Spencer, A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.011 · Cited by 308 · see citing works

BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency

Sun, C., Yin, J., Fang, Y., Chen, J., Jeong, K. J., Chen, X., Vellano, C. P., Ju, Z., Zhao, W., Zhang, D., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.019 · Cited by 302 · see citing works

Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT–mTORC1 activation

Zhang, P., Wang, D., Zhao, Y., Ren, S., Gao, K., Ye, Z., Wang, S., Pan, C.-W., Zhu, Y., Yan, Y., et al. (2017) · Nature Medicine · doi:10.1038/nm.4379 · Cited by 301 · see citing works

Bromodomain inhibitors and cancer therapy: From structures to applications

Pérez-Salvia, M., & Esteller, M. (2016) · Epigenetics · doi:10.1080/15592294.2016.1265710 · Cited by 293 · see citing works

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

Duan, Q., McMahon, S., Anand, P., Shah, H., Thomas, S., Salunga, H. T., Huang, Y., Zhang, R., Sahadevan, A., Lemieux, M. E., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aah5084 · Cited by 262 · see citing works

Brd4 maintains constitutively active NF-κB in cancer cells by binding to acetylated RelA

Zou, Z., Huang, B., Wu, X., Zhang, H., Qi, J., Bradner, J. E., Nair, S. K., & Chen, L.-F. (2013) · Oncogene · doi:10.1038/onc.2013.179 · Cited by 260 · see citing works

BRD4 Sustains Melanoma Proliferation and Represents a New Target for Epigenetic Therapy

Segura, M. F., Fontanals-Cirera, B., Gaziel‐Sovran, A., Guijarro, M. V., Hanniford, D., Zhang, G., González‐Gómez, P., Morante, M., Jubierre, L., Zhang, W., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-0122-t · Cited by 245 · see citing works

Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation

Itzen, F., Greifenberg, A. K., Bösken, C. A., & Geyer, M. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku449 · Cited by 237 · see citing works

Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors

Ember, S. W., Zhu, J.-Y., Olesen, S. H., Martin, M. P., Becker, A., Berndt, N., Georg, G. I., & Schönbrunn, E. (2014) · ACS Chemical Biology · doi:10.1021/cb500072z · Cited by 227 · see citing works

3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

Hewings, D. S., Wang, M., Philpott, M., Fedorov, O., Uttarkar, S., Filippakopoulos, P., Picaud, S., Vuppusetty, C., Marsden, B. D., Knapp, S., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm200640v · Cited by 219 · see citing works

Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials

Albrecht, B. K., Gehling, V. S., Hewitt, M. C., Vaswani, R. G., Côté, A., Leblanc, Y., Nasveschuk, C. G., Bellon, S. F., Bergeron, L., Campbell, R., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01882 · Cited by 218 · see citing works

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Bhadury, J., Nilsson, L. M., Muralidharan, S. V., Green, L. C., Li, Z., Gesner, E. M., Hansen, H. C., Keller, U. B., McLure, K. G., & Nilsson, J. A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1406722111 · Cited by 215 · see citing works

BRD4 is a novel therapeutic target for liver fibrosis

Ding, N., Hah, N., Yu, R. T., Sherman, M. H., Benner, C., Leblanc, M., He, M., Liddle, C., Downes, M., & Evans, R. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1522163112 · Cited by 211 · see citing works

BET Inhibition Silences Expression of MYCN and BCL2 and Induces Cytotoxicity in Neuroblastoma Tumor Models

Wyce, A., Ganji, G., Smitheman, K. N., Chung, C., Korenchuk, S., Bai, Y., Barbash, O., Le, B., Craggs, P. D., McCabe, M. T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072967 · Cited by 208 · see citing works

Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer

Shu, S., Wu, H., Ge, J. Y., Zeid, R., Harris, I. S., Jovanović, B., Murphy, K. C., Wang, B., Qiu, X., Endress, J. E., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.04.027 · Cited by 205 · see citing works

Identification of a Chemical Probe for Bromo and Extra C-Terminal Bromodomain Inhibition through Optimization of a Fragment-Derived Hit

Fish, P. V., Filippakopoulos, P., Bish, G., Brennan, P. E., Bunnage, M. E., Cook, A. S., Federov, O., Gerstenberger, B. S., Jones, H. M., Knapp, S., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3010515 · Cited by 199 · see citing works

Place your BETs: the therapeutic potential of bromodomains

Prinjha, R. K., Witherington, J., & Lee, K. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2011.12.002 · Cited by 197 · see citing works

Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer

Kurimchak, A., Shelton, C., Duncan, K., Johnson, K. J., Brown, J., O’Brien, S. W., Gabbasov, R. T., Fink, L. S., Li, Y., Lounsbury, N., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.091 · Cited by 197 · see citing works

An epigenomic approach to therapy for tamoxifen-resistant breast cancer

Feng, Q. F., Zhang, Z., Shea, M. J., Creighton, C. J., Coarfa, C., Hilsenbeck, S. G., Lanz, R. B., He, B., Wang, L., Fu, X., et al. (2014) · Cell Research · doi:10.1038/cr.2014.71 · Cited by 196 · see citing works

Opposing Functions of BRD4 Isoforms in Breast Cancer

Wu, S.-Y., Lee, C.-F., Lai, H., Yu, C., Lee, J., Zuo, H., Tsai, S. Y., Tsai, M., Ge, K., Wan, Y., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.04.034 · Cited by 195 · see citing works

Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors

Romero, F. A., Taylor, A. M., Crawford, T. D., Tsui, V., Côté, A., & Magnuson, S. R. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01514 · Cited by 194 · see citing works

Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition

Bolden, J. E., Tasdemir, N., Dow, L. E., van Es, J. H., Wilkinson, J. E., Zhao, Z., Clevers, H. C., & Lowe, S. W. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.025 · Cited by 188 · see citing works

Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition

Henssen, A. G., Althoff, K., Odersky, A., Beckers, A., Koche, R. P., Speleman, F., Schäfers, S., Bell, E., Nortmeyer, M., Westermann, F., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1449 · Cited by 186 · see citing works

Histone deacetylase inhibitors as radiosensitisers: effects on DNA damage signalling and repair

Grošelj, B., Sharma, N. L., Hamdy, F. C., Kerr, M., & Kiltie, A. E. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.21 · Cited by 185 · see citing works

Bromodomain Protein BRD4 Is Required for Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription

Nagarajan, S., Hossan, T., Alawi, M., Najafova, Z., Indenbirken, D., Bedi, U., Taipaleenmäki, H., Batalla, I. B., Scheller, M., Loges, S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.06.016 · Cited by 182 · see citing works

Dual-Target Inhibitors Based on HDACs: Novel Antitumor Agents for Cancer Therapy

Liu, T., Wan, Y., Xiao, Y., Xia, C., & Duan, G. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00491 · Cited by 180 · see citing works

Dynamic Chromatin Targeting of BRD4 Stimulates Cardiac Fibroblast Activation

Stratton, M. S., Bagchi, R. A., Felisbino, M. B., Hirsch, R. A., Smith, H. E., Riching, A. S., Enyart, B. Y., Koch, K. A., Cavasin, M. A., Alexanian, M., et al. (2019) · Circulation Research · doi:10.1161/circresaha.119.315125 · Cited by 179 · see citing works

Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia

Dawson, M. A., Gudgin, E. J., Horton, S. J., Giotopoulos, G., Meduri, E., Robson, S. C., Cannizzaro, E., Osaki, H., Wiese, M., Putwain, S., et al. (2013) · Leukemia · doi:10.1038/leu.2013.338 · Cited by 175 · see citing works

DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4

Jin, X., Yan, Y., Wang, D., Ding, D., Ma, T., Ye, Z., Jiménez, R. E., Wang, L., Wu, H., & Huang, H. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.06.036 · Cited by 167 · see citing works

Potent Dual BET/HDAC Inhibitors for Efficient Treatment of Pancreatic Cancer

He, S., Dong, G., Li, Y., Wu, S., Wang, W., & Sheng, C. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.201915896 · Cited by 166 · see citing works

Cyclin-Dependent Kinase Inhibitor Dinaciclib Interacts with the Acetyl-Lysine Recognition Site of Bromodomains

Martin, M. P., Olesen, S. H., Georg, G. I., & Schönbrunn, E. (2013) · ACS Chemical Biology · doi:10.1021/cb4003283 · Cited by 160 · see citing works

Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

Tang, P., Zhang, J., Liu, J., Chiang, C., & Ouyang, L. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01487 · Cited by 153 · see citing works

Brd4 engagement from chromatin targeting to transcriptional regulation: selective contact with acetylated histone H3 and H4

Chiang, C. (2009) · F1000 Biology Reports · doi:10.3410/b1-98 · Cited by 150 · see citing works

Beating the odds: BETs in disease

Wang, C., & Filippakopoulos, P. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.06.002 · Cited by 148 · see citing works

BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer

Li, X., Baek, G., Ramanand, S. G., Sharp, A., Gao, Y., Yuan, W., Welti, J., Rodrigues, D. N., Dolling, D., Figueiredo, I., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.078 · Cited by 148 · see citing works

Discovery of N-Ethyl-4-[2-(4-fluoro-2,6-dimethyl-phenoxy)-5-(1-hydroxy-1-methyl-ethyl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (ABBV-744), a BET Bromodomain Inhibitor with Selectivity for the Second Bromodomain

Sheppard, G. S., Wang, L., Fidanze, S. D., Hasvold, L. A., Liu, D., Pratt, J. K., Park, C. H., Longenecker, K. L., Qiu, W., Torrent, M., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00628 · Cited by 139 · see citing works

Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrityPreprint

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Structures of the Dual Bromodomains of the P-TEFb-activating Protein Brd4 at Atomic Resolution

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Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies

Mahadevan, D., Chiorean, E. G., Harris, W. B., Hoff, D. D. V., Stejskal-Barnett, A., Qi, W., Anthony, S. P., Younger, A., Rensvold, D., Cordova-Marks, F. M., et al. (2012) · European Journal of Cancer · doi:10.1016/j.ejca.2012.06.027 · Cited by 136 · see citing works

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

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Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

Kong, X., Pan, P., Sun, H., Xia, H., Wang, X., Li, Y., & Hou, T. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00446 · Cited by 134 · see citing works

Research Article: Selectivity‐determining Residues in Plk1

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AMPK–ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells

Jang, J. E., Eom, J.-I., Jeung, H.-K., Cheong, J., Lee, J. Y., Kim, J. S., & Min, Y. H. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1903 · Cited by 130 · see citing works

BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

Dey, A., Yang, W., Gégonne, A., Nishiyama, A., Pan, R., Yagi, R., Grinberg, A., Finkelman, F. D., Pfeifer, K. E., Zhu, J., et al. (2019) · The EMBO Journal · doi:10.15252/embj.2018100293 · Cited by 125 · see citing works

The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response

Hussong, M., Börno, S. T., Kerick, M., Wunderlich, A., Franz, A. M., Sültmann, H., Timmermann, B., Lehrach, H. R., Hirsch‐Kauffmann, M., & Schweiger, M. R. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.157 · Cited by 120 · see citing works

The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects

Shahbazi, J., Liu, P. Y., Atmadibrata, B., Bradner, J. E., Marshall, G. M., Lock, R. B., & Liu, T. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1666 · Cited by 120 · see citing works

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

Andrews, F. H., Singh, A. R., Joshi, S., Smith, C. A., Morales, G. A., Garlich, J. R., Durden, D. L., & Kutateladze, T. G. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1613091114 · Cited by 119 · see citing works

The Commonly Used PI3-Kinase Probe LY294002 Is an Inhibitor of BET Bromodomains

Dittmann, A., Werner, T., Chung, C., Savitski, M. M., Savitski, M. F., Grandi, P., Hopf, C., Lindon, M. J., Neubauer, G., Prinjha, R. K., et al. (2013) · ACS Chemical Biology · doi:10.1021/cb400789e · Cited by 118 · see citing works

Make your best BET: The emerging role of BET inhibitor treatment in malignant tumors

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Synergistic effect of JQ 1 and rapamycin for treatment of human osteosarcoma

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Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

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BRD4 Structure–Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536

Chen, L., Yap, J. L., Yoshioka, M., Lanning, M. E., Fountain, R. N., Raje, M. R., Scheenstra, J. A., Strovel, J. W., & Fletcher, S. (2015) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.5b00084 · Cited by 96 · see citing works

GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1

Kumar, K., Raza, S. S., Knab, L. M., Chow, C. R., Kwok, B., Bentrem, D. J., Popovic, R., Ebine, K., Licht, J. D., & Munshi, H. G. (2015) · Scientific Reports · doi:10.1038/srep09489 · Cited by 94 · see citing works

The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

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Discovery of Thieno[2,3-d]pyrimidine-Based Hydroxamic Acid Derivatives as Bromodomain-Containing Protein 4/Histone Deacetylase Dual Inhibitors Induce Autophagic Cell Death in Colorectal Carcinoma Cells

Pan, Z., Li, X., Wang, Y., Jiang, Q., Jiang, L., Zhang, M., Zhang, N., Wu, F., Liu, B., & He, G. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02178 · Cited by 90 · see citing works

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

Chang, X., Sun, D., Shi, D., Wang, G., Chen, Y., Zhang, K., Tan, H., Liu, J., Liu, B., & Ouyang, L. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.06.003 · Cited by 89 · see citing works

Dual-target kinase drug design: Current strategies and future directions in cancer therapy

Sun, D., Zhao, Y., Zhang, S., Zhang, L., Liu, B., & Ouyang, L. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.112025 · Cited by 88 · see citing works

Combined Targeting of the BRD4–NUT–p300 Axis in NUT Midline Carcinoma by Dual Selective Bromodomain Inhibitor, NEO2734

Morrison-Smith, C. D., Knox, T. M., Filic, I., Soroko, K. M., Eschle, B. K., Wilkens, M. K., Gokhale, P. C., Giles, F. J., Griffin, A. M., Brown, B., et al. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0087 · Cited by 86 · see citing works

Recruitment of Brd4 to the Human Papillomavirus Type 16 DNA Replication Complex Is Essential for Replication of Viral DNA

Wang, X., Helfer, C. M., Pancholi, N. J., Bradner, J. E., & You, J. (2013) · Journal of Virology · doi:10.1128/jvi.03068-12 · Cited by 84 · see citing works

Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

Li, C., Bonazzoli, E., Bellone, S., Choi, J., Dong, W., Menderes, G., Altwerger, G. H., Han, C., Manzano, A., Bianchi, A., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1814027116 · Cited by 84 · see citing works

The structure based design of dual HDAC/BET inhibitors as novel epigenetic probes

Atkinson, S. J., Soden, P. E., Angell, D. C., Bantscheff, M., Chung, C., Giblin, K. A., Smithers, N. N., Furze, R. C., Gordon, L. J., Drewes, G., et al. (2014) · MedChemComm · doi:10.1039/c3md00285c · Cited by 76 · see citing works

Dual Screening of BPTF and Brd4 Using Protein-Observed Fluorine NMR Uncovers New Bromodomain Probe Molecules

Urick, A. K., Hawk, L. M. L., Cassel, M. K., Mishra, N. K., Liu, S., Adhikari, N., Zhang, W., dos Santos, C. O., Hall, J. L., & Pomerantz, W. C. K. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00483 · Cited by 76 · see citing works

Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase–Bromodomain Inhibitor

Divakaran, A., Talluri, S., Ayoub, A. M., Mishra, N. K., Cui, H., Widen, J. C., Berndt, N., Zhu, J.-Y., Carlson, A. S., Topczewski, J. J., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01248 · Cited by 76 · see citing works

Antitumor activity of the dual BET and CBP/EP300 inhibitor NEO2734

Spriano, F., Gaudio, E., Cascione, L., Tarantelli, C., Melle, F., Motta, G., Priebe, V., Rinaldi, A., Golino, G., Mensah, A. A., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020001879 · Cited by 76 · see citing works

BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis

Dong, X., Hu, X., Chen, J., Hu, D., & Chen, L.-F. (2018) · Cell Death & Disease · doi:10.1038/s41419-017-0181-6 · Cited by 75 · see citing works

Structure-Based Discovery and Optimization of Benzo[d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC)

Zhang, M., Zhang, Y., Song, M., Xue, X., Wang, J., Wang, C., Zhang, C., Li, C., Xiang, Q., Zou, L., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00103 · Cited by 71 · see citing works

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

Peirs, S., Frismantas, V., Matthijssens, F., Loocke, W. V., Pieters, T., Vandamme, N., Lintermans, B., Dobay, M. P., Berx, G., Poppe, B. G., et al. (2017) · Leukemia · doi:10.1038/leu.2017.10 · Cited by 70 · see citing works

Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains

Wang, J., Erazo, T., Ferguson, F. M., Buckley, D. L., Gómez, N., Muñoz‐Guardiola, P., Diéguez-Martínez, N., Deng, X., Hao, M., Massefski, W. W., et al. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.7b00638 · Cited by 69 · see citing works

Synthesis and evaluation of novel dual BRD4/HDAC inhibitors

Amemiya, S., Yamaguchi, T., Hashimoto, Y., & Noguchi‐Yachide, T. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.04.043 · Cited by 66 · see citing works

Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity

Watts, E., Heidenreich, D. J., Tucker, E. R., Raab, M., Strebhardt, K., Chesler, L., Knapp, S., Bellenie, B. R., & Hoelder, S. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01947 · Cited by 66 · see citing works

Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors

Zhang, Z., Hou, S., Chen, H., Ran, T., Jiang, F., Bian, Y., Zhang, D., Zhi, Y., Wang, L., Zhang, L., et al. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.04.034 · Cited by 63 · see citing works

Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors

Liu, S., Yosief, H. O., Dai, L., Huang, H., Dhawan, G., Zhang, X., Muthengi, A., Roberts, J. M., Buckley, D. L., Perry, J. A., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00765 · Cited by 62 · see citing works

Single Agent and Synergistic Activity of the “First-in-Class” Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma

Singh, A. R., Joshi, S., Burgoyne, A. M., Sicklick, J. K., Ikeda, S., Kono, Y., Garlich, J. R., Morales, G. A., & Durden, D. L. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0976 · Cited by 61 · see citing works

Structure-based design, synthesis and in vitro antiproliferative effects studies of novel dual BRD4/HDAC inhibitors

Shao, M., He, L., Zheng, L., Huang, L., Zhou, Y., Wang, T., Chen, Y., Shen, M., Wang, F., Yang, Z., et al. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.07.054 · Cited by 60 · see citing works

Synthesis and biological activity of N-aryl-2-aminothiazoles: potent pan inhibitors of cyclin-dependent kinases

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Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4

Allen, B. K., Mehta, S., Ember, S. W. J., Schönbrunn, E., Ayad, N. G., & Schürer, S. C. (2015) · Scientific Reports · doi:10.1038/srep16924 · Cited by 59 · see citing works

Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics

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Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes

Chen, J., Li, Y., Zhang, J., Zhang, M., Wei, A., Liu, H., Xie, Z., Ren, W., Duan, W., Zhang, Z., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112868 · Cited by 57 · see citing works

Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents

Cheng, G., Wang, Z., Yang, J., Bao, Y. J., Xu, Q., Zhao, L., & Liu, D. (2018) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2018.12.011 · Cited by 55 · see citing works

Phospho-BRD4: transcription plasticity and drug targeting

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Targeting Super‐Enhancers via Nanoparticle‐Facilitated BRD4 and CDK7 Inhibitors Synergistically Suppresses Pancreatic Ductal Adenocarcinoma

Huang, C., You, X., Dai, C., Xu, Q., Li, F., Wang, L., Huang, X., Wang, J., Li, S., Gao, Z., et al. (2020) · Advanced Science · doi:10.1002/advs.201902926 · Cited by 53 · see citing works

SF2523: Dual PI3K/BRD4 Inhibitor Blocks Tumor Immunosuppression and Promotes Adaptive Immune Responses in Cancer

Joshi, S., Singh, A. R., Liu, K. X., Pham, T. V., Zulcic, M., Skola, D., Chun, H. B., Glass, C. K., Morales, G. A., Garlich, J. R., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-1206 · Cited by 52 · see citing works

Protein targeting chimeric molecules specific for dual bromodomain 4 (BRD4) and Polo-like kinase 1 (PLK1) proteins in acute myeloid leukemia cells

Mu, X., Bai, L., Xu, Y., Wang, J., & Lu, H. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.11.007 · Cited by 52 · see citing works

Dual Kinase-Bromodomain Inhibitors in Anticancer Drug Discovery: A Structural and Pharmacological Perspective

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Characterization of a dual BET / HDAC inhibitor for treatment of pancreatic ductal adenocarcinoma

Zhang, X., Zegar, T., Weiser, T., Hamdan, F. H., Berger, B., Lucas, R., Balourdas, D.-I., Ladigan, S., Cheung, P. F., Liffers, S., et al. (2020) · International Journal of Cancer · doi:10.1002/ijc.33137 · Cited by 52 · see citing works

Validation of the epigenetic reader bromodomain-containing protein 4 (BRD4) as a therapeutic target for treatment of airway remodeling

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2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2 inhibitors

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Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk

Sdelci, S., Lardeau, C.-H., Tallant, C., Klepsch, F., Klaiber, B., Bennett, J. M., Rathert, P., Schuster, M. K., Penz, T., Fedorov, O., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2080 · Cited by 46 · see citing works

Structural Mechanism of the Oxygenase JMJD6 Recognition by the Extraterminal (ET) Domain of BRD4

Konuma, T., Yu, D., Zhao, C., Ju, Y., Sharma, R., Ren, C., Zhang, Q., Zhou, M., & Zeng, L. (2017) · Scientific Reports · doi:10.1038/s41598-017-16588-8 · Cited by 46 · see citing works

Dual BRD4 and AURKA Inhibition Is Synergistic against MYCN-Amplified and Nonamplified Neuroblastoma

Felgenhauer, J., Tomino, L., Selich‐Anderson, J., Bopp, E., & Shah, N. (2018) · Neoplasia · doi:10.1016/j.neo.2018.08.002 · Cited by 43 · see citing works

MUC15 inhibits cancer metastasis via PI3K/AKT signaling in renal cell carcinoma

Yue, Y., Hui, K., Wu, S., Zhang, M., Que, T., Gu, Y., Wang, X., Wu, K., & Fan, J. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2518-9 · Cited by 43 · see citing works

Targeting polo-like kinase 1 in acute myeloid leukemia

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BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

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Design, synthesis, and biological evaluation of 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as novel dual-PLK1/BRD4 inhibitors

Wang, N., Xu, Y. X., Xiao, K.-J., Zuo, W., Zhu, Y., Hu, R., Wang, W., Shi, Y.-J., Yu, L., & Liu, Z. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112152 · Cited by 38 · see citing works

Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer

Coleman, D. J., Gao, L., Schwartzman, J. A., Korkola, J. E., Sampson, D., Derrick, D. S., Urrutia, J. A., Balter, A. I., Burchard, J., King, C. J., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-40518-5 · Cited by 37 · see citing works

Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation

Gaub, A., Sheikh, B. N., Basilicata, M. F., Vincent, M., Nizon, M., Colson, C., Bird, M., Bradner, J. E., Thévenon, J., Boutros, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16103-0 · Cited by 37 · see citing works

Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs

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Dual targeting of bromodomain-containing 4 by AZD5153 and BCL2 by AZD4320 against B-cell lymphomas concomitantly overexpressing c-MYC and BCL2

Takimoto‐Shimomura, T., Tsukamoto, T., Maegawa, S., Fujibayashi, Y., Matsumura‐Kimoto, Y., Mizuno, Y., Chinen, Y., Shimura, Y., Mizutani, S., Horiike, S., et al. (2018) · Investigational New Drugs · doi:10.1007/s10637-018-0623-8 · Cited by 33 · see citing works

The novel dual BET/HDAC inhibitor TW09 mediates cell death by mitochondrial apoptosis in rhabdomyosarcoma cells

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Targeting both BET and CBP/EP300 proteins with the novel dual inhibitors NEO2734 and NEO1132 leads to anti‐tumor activity in multiple myeloma

Ryan, K. R., Giles, F. J., & Morgan, G. J. (2020) · European Journal Of Haematology · doi:10.1111/ejh.13525 · Cited by 30 · see citing works

Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation

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Downregulation of BRD4 inhibits gallbladder cancer proliferation and metastasis and induces apoptosis via PI3K/AKT pathway

Hao, J., Yang, Z., Wang, L., Zhang, Y., Shu, Y., Jiang, L., Hu, Y., Lv, W., Dong, P., & Liu, Y. (2017) · International Journal of Oncology · doi:10.3892/ijo.2017.4081 · Cited by 28 · see citing works

The role of ZA channel water-mediated interactions in the design of bromodomain-selective BET inhibitors

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Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors

Timme, N., Han, Y., Liu, S., Yosief, H. O., García, H. D., Bei, Y., Klironomos, F., MacArthur, I. C., Szymansky, A., von Stebut, J., et al. (2019) · Translational Oncology · doi:10.1016/j.tranon.2019.09.013 · Cited by 28 · see citing works

Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics

Prieto-Martínez, F. D., & Medina‐Franco, J. L. (2018) · Biomolecules · doi:10.3390/biom8030061 · Cited by 25 · see citing works

Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases

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Dual PI3K-BRD4 Inhibitor SF1126 Inhibits Colorectal Cancer Cell Growth in Vitro and in Vivo

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BindingDB (2026) · UC San Diego · doi:10.7270/q2hq44s0

BindingDB Entry 50019841: From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors.

BindingDB (2024) · UC San Diego · doi:10.7270/q2k93cxs

BindingDB Entry 50020982: New Strategies for Responding to SARS-CoV-2: The Present and Future of Dual-Target Drugs.

BindingDB (2025) · UC San Diego · doi:10.7270/q22v2mqg

BindingDB Entry 50022801: Targeting bromodomian-containing protein 8 (BRD8): An advanced tool to interrogate BRD8.

BindingDB (2026) · UC San Diego · doi:10.7270/q27m0ds8

BindingDB Entry 50015477: Discovery of Novel Dual-Target Inhibitor of Bromodomain-Containing Protein 4/Casein Kinase 2 Inducing Apoptosis and Autophagy-Associated Cell Death for Triple-Negative Breast Cancer Therapy.

BindingDB (2023) · UC San Diego · doi:10.7270/q25d8wrz

BindingDB Entry 50023792: Discovery of dual CDK4/6 and BRD4 inhibitor as apoptosis and autophagy inducers against NSCLC in vitro and in vivo.

BindingDB (2026) · UC San Diego · doi:10.7270/q2gb290w

BindingDB Entry 50017847: Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy.

BindingDB (2023) · UC San Diego · doi:10.7270/q2x06c52

BindingDB Entry 50021383: Molecular Transformers: Adaptive Multitarget Ligands for Esterase-Induced Transition from Analgesics to Anesthetics.

BindingDB (2025) · UC San Diego · doi:10.7270/q2dr313t

BindingDB Entry 50021506: Dual inhibitors of HDAC and other epigenetic regulators: A novel strategy for cancer treatment.

BindingDB (2025) · UC San Diego · doi:10.7270/q29k4gvs

BindingDB Entry 50023398: Marine natural product-inspired discovery of novel BRD4 inhibitors with anti-inflammatory activity.

BindingDB (2026) · UC San Diego · doi:10.7270/q24x5dqf

Dual-target inhibitors of bromodomain-containing protein 4 (BRD4) in cancer therapy: Current situation and future directions

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