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Exploring Selective Inhibition of the First Bromodomain of the Human Bromodomain and Extra-terminal Domain (BET) Proteins

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Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105, 13273 Marseille, France
Department of Organic Chemistry, Lobachevsky State University of Nizhni Novgorod, Gagarina av. 23, Nizhni Novgorod 603950, Russia
§ Screening Platform AD2P, CNRS, AFMB UMR 7257, Aix-Marseille Université, 13288 Marseille, France
Cisbio Bioassays, R&D, Parc Marcel Boiteux, BP 84175, 30200 Codolet, France
Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, U.K.
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
Goethe-University, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Science, Campus Riedberg, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany
*S.C. E-mail: [email protected]. Phone: (+33)491-835-551.
*X.M. E-mail: [email protected]. Phone: (+33)486-977-331. Mailing address: Centre de Recherche en Cancérologie de Marseille (CRCM); INSERM U1068; CNRS UMR7258; Aix-Marseille Université UM105 & Institut Paoli Calmettes, 27 Boulevard Leï Roure CS30059, 13273 Marseille Cedex 9, France.
Cite this: J. Med. Chem. 2016, 59, 4, 1634–1641
Publication Date (Web):January 6, 2016
https://doi.org/10.1021/acs.jmedchem.5b01708
Copyright © 2016 American Chemical Society

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    Abstract

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    A midthroughput screening follow-up program targeting the first bromodomain of the human BRD4 protein, BRD4(BD1), identified an acetylated-mimic xanthine derivative inhibitor. This compound binds with an affinity in the low micromolar range yet exerts suitable unexpected selectivity in vitro against the other members of the bromodomain and extra-terminal domain (BET) family. A structure-based program pinpointed a role of the ZA loop, paving the way for the development of potent and selective BET-BRDi probes.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b01708.

    • Additional figures, schemes, and tables and detailed experimental procedures for biochemistry, biology, and chemistry including spectral data and structures of synthesized compounds (PDF)

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    Accession Codes

    PDB codes for BRD4(BD1) with bound 1, 5 and 7, respectively, are 5EGU, 5EIS, and 5EI4.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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    17. Laurent Hoffer, Yuliia V. Voitovich, Brigitt Raux, Kendall Carrasco, Christophe Muller, Aleksey Y. Fedorov, Carine Derviaux, Agnès Amouric, Stéphane Betzi, Dragos Horvath, Alexandre Varnek, Yves Collette, Sébastien Combes, Philippe Roche, Xavier Morelli. Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach. Journal of Medicinal Chemistry 2018, 61 (13) , 5719-5732. https://doi.org/10.1021/acs.jmedchem.8b00653
    18. Robert P. Law, Stephen J. Atkinson, Paul Bamborough, Chun-wa Chung, Emmanuel H. Demont, Laurie J. Gordon, Matthew Lindon, Rab K. Prinjha, Allan J. B. Watson, David J. Hirst. Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain. Journal of Medicinal Chemistry 2018, 61 (10) , 4317-4334. https://doi.org/10.1021/acs.jmedchem.7b01666
    19. Alex M. Ayoub, Laura M. L. Hawk, Ryan J. Herzig, Jiewei Jiang, Andrea J. Wisniewski, Clifford T. Gee, Peiliang Zhao, Jin-Yi Zhu, Norbert Berndt, Nana K. Offei-Addo, Thomas G. Scott, Jun Qi, James E. Bradner, Timothy R. Ward, Ernst Schönbrunn, Gunda I. Georg, and William C. K. Pomerantz . BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen. Journal of Medicinal Chemistry 2017, 60 (12) , 4805-4817. https://doi.org/10.1021/acs.jmedchem.6b01336
    20. Zhiqing Liu, Pingyuan Wang, Haiying Chen, Eric A. Wold, Bing Tian, Allan R. Brasier, and Jia Zhou . Drug Discovery Targeting Bromodomain-Containing Protein 4. Journal of Medicinal Chemistry 2017, 60 (11) , 4533-4558. https://doi.org/10.1021/acs.jmedchem.6b01761
    21. Zhongyi Zeng, Hongming Jin, Jin Xie, Bing Tian, Matthias Rudolph, Frank Rominger, and A. Stephen K. Hashmi . α-Imino Gold Carbenes from 1,2,4-Oxadiazoles: Atom-Economical Access to Fully Substituted 4-Aminoimidazoles. Organic Letters 2017, 19 (5) , 1020-1023. https://doi.org/10.1021/acs.orglett.7b00001
    22. Luca Carlino and Giulio Rastelli . Dual Kinase-Bromodomain Inhibitors in Anticancer Drug Discovery: A Structural and Pharmacological Perspective. Journal of Medicinal Chemistry 2016, 59 (20) , 9305-9320. https://doi.org/10.1021/acs.jmedchem.6b00438
    23. Zhi-Qiang Wang, Zhao-Cong Zhang, Yu-Yang Wu, Ya-Nan Pi, Sheng-Han Lou, Tian-Bo Liu, Ge Lou, Chang Yang. Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy. Signal Transduction and Targeted Therapy 2023, 8 (1) https://doi.org/10.1038/s41392-023-01647-6
    24. Pavle Stojković, Ana Kostić, Ema Lupšić, Nataša Terzić Jovanović, Miroslav Novaković, Paraskev Nedialkov, Antoaneta Trendafilova, Milica Pešić, Igor M. Opsenica. Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells. Bioorganic Chemistry 2023, 138 , 106605. https://doi.org/10.1016/j.bioorg.2023.106605
    25. Aishwarya H. Arole, Prashant Deshmukh, Ashok Sridhar, Shruti Mathur, Mahesh Mahalingaswamy, Hosahalli Subramanya, Nandakumar Dalavaikodihalli Nanjaiah, Balasundaram Padmanabhan. Structural and biochemical insights into purine-based drug molecules in hBRD2 delineate a unique binding mode opening new vistas in the design of inhibitors of the BET family. Acta Crystallographica Section D Structural Biology 2023, 79 (8) , 758-774. https://doi.org/10.1107/S2059798323005211
    26. Anand Divakaran, Daniel A. Harki, William C. K. Pomerantz. Recent progress and structural analyses of domain‐selective BET inhibitors. Medicinal Research Reviews 2023, 43 (4) , 972-1018. https://doi.org/10.1002/med.21942
    27. Süleyman Selim Çınaroğlu, Philip C. Biggin. The role of loop dynamics in the prediction of ligand–protein binding enthalpy. Chemical Science 2023, 14 (24) , 6792-6805. https://doi.org/10.1039/D2SC06471E
    28. Xing-Jie Dai, Lei-Peng Xue, Shi-Kun Ji, Ying Zhou, Ya Gao, Yi-Chao Zheng, Hui-Min Liu, Hong-Min Liu. Triazole-fused pyrimidines in target-based anticancer drug discovery. European Journal of Medicinal Chemistry 2023, 249 , 115101. https://doi.org/10.1016/j.ejmech.2023.115101
    29. Vijay Kumar Bhardwaj, Pralay Das, Rituraj Purohit. Integrating microsecond timescale classical and biased molecular dynamics simulations to screen potential molecules for BRD4-BD1. Chaos, Solitons & Fractals 2023, 167 , 113061. https://doi.org/10.1016/j.chaos.2022.113061
    30. Ram K. Modukuri, Zhifeng Yu, Zhi Tan, Hai Minh Ta, Melek Nihan Ucisik, Zhuang Jin, Justin L. Anglin, Kiran L. Sharma, Pranavanand Nyshadham, Feng Li, Kevin Riehle, John C. Faver, Kevin Duong, Sureshbabu Nagarajan, Nicholas Simmons, Stephen S. Palmer, Mingxing Teng, Damian W. Young, Joanna S. Yi, Choel Kim, Martin M. Matzuk. Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections. Proceedings of the National Academy of Sciences 2022, 119 (22) https://doi.org/10.1073/pnas.2122506119
    31. Anna-Theresa Blasl, Sabrina Schulze, Chuan Qin, Leonie G. Graf, Robert Vogt, Michael Lammers. Post-translational lysine ac(et)ylation in health, ageing and disease. Biological Chemistry 2022, 403 (2) , 151-194. https://doi.org/10.1515/hsz-2021-0139
    32. Yuantao Fu, Yanzhi Zhang, Haiying Sun. Progress in the development of domain selective inhibitors of the bromo and extra terminal domain family (BET) proteins. European Journal of Medicinal Chemistry 2021, 226 , 113853. https://doi.org/10.1016/j.ejmech.2021.113853
    33. Shivani Gokani, Lokesh Kumar Bhatt. Bromodomains: A novel target for the anticancer therapy. European Journal of Pharmacology 2021, 911 , 174523. https://doi.org/10.1016/j.ejphar.2021.174523
    34. Vladimir V. Baranov, Tatyana N. Vol'khina, Yulia V. Nelyubina, Angelina N. Kravchenko. New aspects of reactions of methyl (thio)ureas with benzil. Mendeleev Communications 2021, 31 (5) , 673-676. https://doi.org/10.1016/j.mencom.2021.09.027
    35. Guan-Jun Yang, Ying-Qi Song, Wanhe Wang, Quan-Bin Han, Dik-Lung Ma, Chung-Hang Leung. An optimized BRD4 inhibitor effectively eliminates NF-κB-driven triple-negative breast cancer cells. Bioorganic Chemistry 2021, 114 , 105158. https://doi.org/10.1016/j.bioorg.2021.105158
    36. Kai-Chun Li, Enrico Girardi, Felix Kartnig, Sarah Grosche, Tea Pemovska, Johannes W. Bigenzahn, Ulrich Goldmann, Vitaly Sedlyarov, Ariel Bensimon, Sandra Schick, Jung-Ming G. Lin, Bettina Gürtl, Daniela Reil, Kristaps Klavins, Stefan Kubicek, Sara Sdelci, Giulio Superti-Furga. Cell-surface SLC nucleoside transporters and purine levels modulate BRD4-dependent chromatin states. Nature Metabolism 2021, 3 (5) , 651-664. https://doi.org/10.1038/s42255-021-00386-8
    37. Huarui Cui, Anand Divakaran, Anil K. Pandey, Jorden A. Johnson, Huda Zahid, Zachariah J. Hoell, Mikael O. Ellingson, Ke Shi, Hideki Aihara, Daniel A. Harki, William C. K. Pomerantz. Selective N‐Terminal BET Bromodomain Inhibitors by Targeting Non‐Conserved Residues and Structured Water Displacement**. Angewandte Chemie 2021, 133 (3) , 1240-1246. https://doi.org/10.1002/ange.202008625
    38. Huarui Cui, Anand Divakaran, Anil K. Pandey, Jorden A. Johnson, Huda Zahid, Zachariah J. Hoell, Mikael O. Ellingson, Ke Shi, Hideki Aihara, Daniel A. Harki, William C. K. Pomerantz. Selective N‐Terminal BET Bromodomain Inhibitors by Targeting Non‐Conserved Residues and Structured Water Displacement**. Angewandte Chemie International Edition 2021, 60 (3) , 1220-1226. https://doi.org/10.1002/anie.202008625
    39. Mohd. Muddassir, Kunjal Soni, Chetan B. Sangani, Abdullah Alarifi, Mohd. Afzal, Naaser A. Y. Abduh, Yongtao Duan, Poonam Bhadja. Bromodomain and BET family proteins as epigenetic targets in cancer therapy: their degradation, present drugs, and possible PROTACs. RSC Advances 2021, 11 (2) , 612-636. https://doi.org/10.1039/D0RA07971E
    40. Michael D. Olp, Huarui Cui, William C. K. Pomerantz, Brian C. Smith. Pharmacological Regulation and Functional Significance of Chromatin Binding by BET Tandem Bromodomains. 2020, 209-248. https://doi.org/10.1039/9781788016544-00209
    41. Sergio Pinheiro, Erick M. C. Pinheiro, Estela M. F. Muri, Jaqueline C. Pessôa, Mayara A. Cadorini, Sandro J. Greco. Biological activities of [1,2,4]triazolo[1,5-a]pyrimidines and analogs. Medicinal Chemistry Research 2020, 29 (10) , 1751-1776. https://doi.org/10.1007/s00044-020-02609-1
    42. Qifei Li, Jieming Li, Yan Cai, Yuxing Zou, Bin Chen, Feng Zou, Jiaxian Mo, Ting Han, Weiwei Guo, Wenlong Huang, Qianqian Qiu, Hai Qian. Design, synthesis and biological evaluation of novel 6-phenyl-1,3a,4,10b-tetrahydro-2H-benzo[c]thiazolo[4,5-e]azepin-2-one derivatives as potential BRD4 inhibitors. Bioorganic & Medicinal Chemistry 2020, 28 (15) , 115601. https://doi.org/10.1016/j.bmc.2020.115601
    43. Massimo Petretich, Emmanuel H. Demont, Paola Grandi. Domain-selective targeting of BET proteins in cancer and immunological diseases. Current Opinion in Chemical Biology 2020, 57 , 184-193. https://doi.org/10.1016/j.cbpa.2020.02.003
    44. Junjie Zhong, Jason Riordon, Tony C. Wu, Harrison Edwards, Aaron R. Wheeler, Keith Pardee, Alán Aspuru-Guzik, David Sinton. When robotics met fluidics. Lab on a Chip 2020, 20 (4) , 709-716. https://doi.org/10.1039/C9LC01042D
    45. Y. Wang, L.F. Wang, L.L. Zhang, H.B. Sun, J. Zhao. Molecular mechanism of inhibitor bindings to bromodomain-containing protein 9 explored based on molecular dynamics simulations and calculations of binding free energies. SAR and QSAR in Environmental Research 2020, 31 (2) , 149-170. https://doi.org/10.1080/1062936X.2019.1701075
    46. Fernando D. Prieto-Martínez, José L. Medina-Franco. Current advances on the development of BET inhibitors: insights from computational methods. 2020, 127-180. https://doi.org/10.1016/bs.apcsb.2020.06.002
    47. Matthias Schiedel, Mustafa Moroglu, David M. H. Ascough, Anna E. R. Chamberlain, Jos J. A. G. Kamps, Angelina R. Sekirnik, Stuart J. Conway. Chemische Epigenetik: der Einfluss chemischer und chemo‐biologischer Techniken auf die Zielstruktur‐Validierung von Bromodomänen. Angewandte Chemie 2019, 131 (50) , 18096-18120. https://doi.org/10.1002/ange.201812164
    48. Matthias Schiedel, Mustafa Moroglu, David M. H. Ascough, Anna E. R. Chamberlain, Jos J. A. G. Kamps, Angelina R. Sekirnik, Stuart J. Conway. Chemical Epigenetics: The Impact of Chemical and Chemical Biology Techniques on Bromodomain Target Validation. Angewandte Chemie International Edition 2019, 58 (50) , 17930-17952. https://doi.org/10.1002/anie.201812164
    49. Mohammad Hossein Abdollahi-Basir, Farhad Shirini, Hassan Tajik, Mohammad Ali Ghasemzadeh. A facile and regioselective synthesis of some new pyrimido[4,5-d][1,2,4]triazolo[1,5-a]pyrimidinediones catalyzed by Zn(BDC)-MOF under ultrasound irradiation. Journal of Molecular Structure 2019, 1195 , 302-308. https://doi.org/10.1016/j.molstruc.2019.05.132
    50. Andrea G. Cochran, Andrew R. Conery, Robert J. Sims. Bromodomains: a new target class for drug development. Nature Reviews Drug Discovery 2019, 18 (8) , 609-628. https://doi.org/10.1038/s41573-019-0030-7
    51. Killian Oukoloff, Bobby Lucero, Karol R. Francisco, Kurt R. Brunden, Carlo Ballatore. 1,2,4-Triazolo[1,5-a]pyrimidines in drug design. European Journal of Medicinal Chemistry 2019, 165 , 332-346. https://doi.org/10.1016/j.ejmech.2019.01.027
    52. Jing Su, Xinguo Liu, Shaolong Zhang, Fangfang Yan, Qinggang Zhang, Jianzhong Chen. Insight into selective mechanism of class of I‐BRD9 inhibitors toward BRD9 based on molecular dynamics simulations. Chemical Biology & Drug Design 2019, 93 (2) , 163-176. https://doi.org/10.1111/cbdd.13398
    53. Qianqian Wang, Ying Li, Jiahui Xu, Yuwei Wang, Danfeng Shi, Liang Liu, Elaine Lai‐Han Leung, Xiaojun Yao. Computational study on the selective inhibition mechanism of MS402 to the first and second bromodomains of BRD4. Proteins: Structure, Function, and Bioinformatics 2019, 87 (1) , 3-11. https://doi.org/10.1002/prot.25611
    54. Gunther Fischer. Recent advances in 1,2,4-triazolo[1,5-a]pyrimidine chemistry. 2019, 1-101. https://doi.org/10.1016/bs.aihch.2018.10.002
    55. Marcel Scheepstra, Koen F.W. Hekking, Luc van Hijfte, Rutger H.A. Folmer. Bivalent Ligands for Protein Degradation in Drug Discovery. Computational and Structural Biotechnology Journal 2019, 17 , 160-176. https://doi.org/10.1016/j.csbj.2019.01.006
    56. R. Tumdam, A. Kumar, N. Subbarao, B.S. Balaji. In silico study directed towards identification of novel high-affinity inhibitors targeting an oncogenic protein: BRD4-BD1. SAR and QSAR in Environmental Research 2018, 29 (12) , 975-996. https://doi.org/10.1080/1062936X.2018.1537301
    57. Fang Xie, Mei Huang, Xiansheng Lin, Chenhai Liu, Zhen Liu, Futao Meng, Chao Wang, Qiang Huang. RETRACTED ARTICLE: The BET inhibitor I-BET762 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine. Scientific Reports 2018, 8 (1) https://doi.org/10.1038/s41598-018-26496-0
    58. Yingchao Duan, Yuanyuan Guan, Wenping Qin, Xiaoyu Zhai, Bin Yu, Hongmin Liu. Targeting Brd4 for cancer therapy: inhibitors and degraders. MedChemComm 2018, 9 (11) , 1779-1802. https://doi.org/10.1039/C8MD00198G
    59. Laurent Hoffer, Christophe Muller, Philippe Roche, Xavier Morelli. Chemistry‐driven Hit‐to‐lead Optimization Guided by Structure‐based Approaches. Molecular Informatics 2018, 37 (9-10) https://doi.org/10.1002/minf.201800059
    60. Young Hun Kim, Minsung Kim, Miyoun Yoo, Ji Eun Kim, Heung Kyoung Lee, Jung-Nyoung Heo, Chong Ock Lee, Minjin Yoo, Kwan-Young Jung, Chang-Soo Yun, Sung Woong Moon, Hye Kyung Chang, Chul-Woong Chung, Suhkneung Pyo, Sang Un Choi, Chi Hoon Park. A natural compound, aristoyagonine, is identified as a potent bromodomain inhibitor by mid-throughput screening. Biochemical and Biophysical Research Communications 2018, 503 (2) , 882-887. https://doi.org/10.1016/j.bbrc.2018.06.091
    61. Zhiqing Liu, Bing Tian, Haiying Chen, Pingyuan Wang, Allan R. Brasier, Jia Zhou. Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation. European Journal of Medicinal Chemistry 2018, 151 , 450-461. https://doi.org/10.1016/j.ejmech.2018.04.006
    62. Jing Su, Xinguo Liu, Shaolong Zhang, Fangfang Yan, Qinggang Zhang, Jianzhong Chen. A theoretical insight into selectivity of inhibitors toward two domains of bromodomain‐containing protein 4 using molecular dynamics simulations. Chemical Biology & Drug Design 2018, 91 (3) , 828-840. https://doi.org/10.1111/cbdd.13148
    63. Guoyi Yan, Manzhou Hou, Jiang Luo, Chunlan Pu, Xueyan Hou, Suke Lan, Rui Li. Pharmacophore‐based virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation for the discovery of novel BRD 4 inhibitors. Chemical Biology & Drug Design 2018, 91 (2) , 478-490. https://doi.org/10.1111/cbdd.13109
    64. Zhenyuan Miao, Xianghong Guan, Jiewei Jiang, Gunda I. Georg. BRDT Inhibitors for Male Contraceptive Drug Discovery: Current Status. 2018, 287-315. https://doi.org/10.1007/978-981-13-0773-7_11
    65. A. C. Runcie, M. Zengerle, K.-H. Chan, A. Testa, L. van Beurden, M. G. J. Baud, O. Epemolu, L. C. J. Ellis, K. D. Read, V. Coulthard, A. Brien, A. Ciulli. Optimization of a “bump-and-hole” approach to allele-selective BET bromodomain inhibition. Chemical Science 2018, 9 (9) , 2452-2468. https://doi.org/10.1039/C7SC02536J
    66. Dequina A. Nicholas, Guillaume Andrieu, Katherine J. Strissel, Barbara S. Nikolajczyk, Gerald V. Denis. BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer. Cellular and Molecular Life Sciences 2017, 74 (2) , 231-243. https://doi.org/10.1007/s00018-016-2320-0
    67. Chunyan Cheng, Hongjuan Diao, Fan Zhang, Yongheng Wang, Kai Wang, Ruibo Wu. Deciphering the mechanisms of selective inhibition for the tandem BD1/BD2 in the BET-bromodomain family. Physical Chemistry Chemical Physics 2017, 19 (35) , 23934-23941. https://doi.org/10.1039/C7CP04608A
    68. Yifei Yang, Leilei Zhao, Bin Xu, LingYun Yang, Jian Zhang, Huibin Zhang, Jinpei Zhou. Design, synthesis and biological evaluation of dihydroquinoxalinone derivatives as BRD4 inhibitors. Bioorganic Chemistry 2016, 68 , 236-244. https://doi.org/10.1016/j.bioorg.2016.08.009
    69. Carles Galdeano, Alessio Ciulli. Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology. Future Medicinal Chemistry 2016, 8 (13) , 1655-1680. https://doi.org/10.4155/fmc-2016-0059
    70. Olesya A. Kharenko, Emily M. Gesner, Reena G. Patel, Karen Norek, Andre White, Eric Fontano, Robert K. Suto, Peter R. Young, Kevin G. McLure, Henrik C. Hansen. RVX-297- a novel BD2 selective inhibitor of BET bromodomains. Biochemical and Biophysical Research Communications 2016, 477 (1) , 62-67. https://doi.org/10.1016/j.bbrc.2016.06.021
    71. Jun-lan Yu, Tian-tian Chen, Chen Zhou, Fu-lin Lian, Xu-long Tang, Yi Wen, Jing-kang Shen, Ye-chun Xu, Bing Xiong, Nai-xia Zhang. NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds. Acta Pharmacologica Sinica 2016, 37 (7) , 984-993. https://doi.org/10.1038/aps.2016.19
    72. Anirban Ghoshal, D. Yugandhar, Ajay Kumar Srivastava. BET inhibitors in cancer therapeutics: a patent review. Expert Opinion on Therapeutic Patents 2016, 26 (4) , 505-522. https://doi.org/10.1517/13543776.2016.1159299
    73. Guillaume Andrieu, Anna C. Belkina, Gerald V. Denis. Clinical trials for BET inhibitors run ahead of the science. Drug Discovery Today: Technologies 2016, 19 , 45-50. https://doi.org/10.1016/j.ddtec.2016.06.004
    74. Jamel Meslamani, Steven G. Smith, Roberto Sanchez, Ming-Ming Zhou. Structural features and inhibitors of bromodomains. Drug Discovery Today: Technologies 2016, 19 , 3-15. https://doi.org/10.1016/j.ddtec.2016.09.001

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