ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Inhibitors of the Interaction of a Thyroid Hormone Receptor and Coactivators:  Preliminary Structure−Activity Relationships

View Author Information
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, and University of California San Francisco, Department Biochemistry and Biophysics, 600 Sixteenth Street, San Francisco, California 94143
Cite this: J. Med. Chem. 2007, 50, 22, 5269–5280
Publication Date (Web):October 5, 2007
Copyright © 2007 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    Abstract Image

    The modulation of gene regulation by blocking the interaction between the thyroid receptor (TR) and obligate coregulators has been reported recently with the discovery of the lead compound 3-(dimethylamino)-1-(4-hexylphenyl)propan-1-one). Herein we report studies aimed at optimization of this initial hit to determine the basic parameters of the structure−activity relationships and clarify the mechanism of action. These studies provided new insights, showing that activity and TRβ isoform selectivity is highly correlated with the structural composition of these covalent inhibitors.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

     St. Jude's Children's Research Hospital.

     University of California, San Francisco.


     Corresponding author. Address:  St. Jude Children's Research Hospital, Department of Chemical Biology and Therapeutics, 332 N. Lauderdale St., Memphis TN 38104-2794. Tel:  (901) 495 5714. Fax:  (901) 495-5715. E-mail:  [email protected].

    Supporting Information Available

    Jump To

    Experimental procedures and characterization data for 3bk, 4ag, 5cf, 6cf, 6bm, 7bg, 8b, and 8e. This material is available free of charge via the Internet at

    Terms & Conditions

    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:

    Cited By

    This article is cited by 37 publications.

    1. Dishary Sharmin, Branka Divović, Xingjie Ping, Rok Cerne, Jodi L. Smith, Sepideh Rezvanian, Prithu Mondal, Michelle Jean Meyer, Molly E. Kiley, Leggy A. Arnold, Md Yeunus Mian, Kamal P. Pandey, Xiaoming Jin, Jelena R. Mitrović, Djordje Djorović, Arnold Lippa, James M. Cook, Lalit K. Golani, Petra Scholze, Miroslav M. Savić, Jeffrey M. Witkin. New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy. ACS Chemical Neuroscience 2024, 15 (3) , 517-526.
    2. Matthias Gehringer, Stefan A. Laufer. Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology. Journal of Medicinal Chemistry 2019, 62 (12) , 5673-5724.
    3. Premchendar Nandhikonda, Wen Z. Lynt, Megan M. McCallum, Tahniyath Ara, Athena M. Baranowski, Nina Y. Yuan, Dana Pearson, Daniel D. Bikle, R. Kiplin Guy, and Leggy A. Arnold . Discovery of the First Irreversible Small Molecule Inhibitors of the Interaction between the Vitamin D Receptor and Coactivators. Journal of Medicinal Chemistry 2012, 55 (10) , 4640-4651.
    4. Jong Yeon Hwang, Ramy R. Attia, Fangyi Zhu, Lei Yang, Andrew Lemoff, Cynthia Jeffries, Michele C. Connelly, and R. Kiplin Guy . Synthesis and Evaluation of Sulfonylnitrophenylthiazoles (SNPTs) as Thyroid Hormone Receptor–Coactivator Interaction Inhibitors. Journal of Medicinal Chemistry 2012, 55 (5) , 2301-2310.
    5. Prabodh Sadana, Jong Yeon Hwang, Ramy R. Attia, Leggy A. Arnold, Geoffrey Neale, and R. Kiplin Guy . Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor. ACS Chemical Biology 2011, 6 (10) , 1096-1106.
    6. Caterina Carmi, Andrea Cavazzoni, Stefano Vezzosi, Fabrizio Bordi, Federica Vacondio, Claudia Silva, Silvia Rivara, Alessio Lodola, Roberta R. Alfieri, Silvia La Monica, Maricla Galetti, Andrea Ardizzoni, Pier Giorgio Petronini and Marco Mor . Novel Irreversible Epidermal Growth Factor Receptor Inhibitors by Chemical Modulation of the Cysteine-Trap Portion. Journal of Medicinal Chemistry 2010, 53 (5) , 2038-2050.
    7. Jong Yeon Hwang, Leggy A. Arnold, Fangyi Zhu, Aaron Kosinski, Thomas J. Mangano, Vincent Setola, Bryan L. Roth and R. Kiplin Guy. Improvement of Pharmacological Properties of Irreversible Thyroid Receptor Coactivator Binding Inhibitors. Journal of Medicinal Chemistry 2009, 52 (13) , 3892-3901.
    8. Michele H. Potashman and Mark E. Duggan. Covalent Modifiers: An Orthogonal Approach to Drug Design. Journal of Medicinal Chemistry 2009, 52 (5) , 1231-1246.
    9. Leyla Celik, Julie Davey Dalsgaard Lund and Birgit Schiøtt. Exploring Interactions of Endocrine-Disrupting Compounds with Different Conformations of the Human Estrogen Receptor α Ligand Binding Domain: A Molecular Docking Study. Chemical Research in Toxicology 2008, 21 (11) , 2195-2206.
    10. Nikita V. Tolstoluzhsky, Nikolay Yu. Gorobets, Nadezhda N. Kolos and Sergey M. Desenko . Efficient Ytterbium Triflate Catalyzed Microwave-Assisted Synthesis of 3-Acylacrylic Acid Building Blocks. Journal of Combinatorial Chemistry 2008, 10 (6) , 893-896.
    11. Huan Yan, Zhanyan Liu, Guibin Lin, Fei Gu, Yan Liu, Yuxiao Xu, Xueli Kuang, Yuan Zhang. Systemic delivery of gemcitabine analogue and STAT3 siRNA promotes antitumor immunity against melanoma. Nano Research 2022, 15 (10) , 9057-9072.
    12. Hongyan Du, Dejun Jiang, Junbo Gao, Xujun Zhang, Lingxiao Jiang, Yundian Zeng, Zhenxing Wu, Chao Shen, Lei Xu, Dongsheng Cao, Tingjun Hou, Peichen Pan. Proteome-Wide Profiling of the Covalent-Druggable Cysteines with a Structure-Based Deep Graph Learning Network. Research 2022, 2022
    13. Mélanie Uguen, Conghao Gai, Lukas J. Sprenger, Hang Liu, Andrew G. Leach, Michael J. Waring. Microwave-assisted synthesis of 4-oxo-2-butenoic acids by aldol-condensation of glyoxylic acid. RSC Advances 2021, 11 (48) , 30229-30236.
    14. Kornelia J. Skowron, Kenneth Booker, Changfeng Cheng, Simone Creed, Brian P. David, Phillip R. Lazzara, Amy Lian, Zamia Siddiqui, Thomas E. Speltz, Terry W. Moore. Steroid receptor/coactivator binding inhibitors: An update. Molecular and Cellular Endocrinology 2019, 493 , 110471.
    15. Sejin An, Da Yoon Moon, Bong Ser Park. Solvent free, light induced 1,2-bromine shift reaction of α-bromo ketones. Tetrahedron 2018, 74 (48) , 6922-6928.
    16. Rekha Kumari, Anitha Varghese, K. B. Akshaya, Louis George, Prajwal Lourdes Lobo. Influence of Solvent Environment on the Photophysical Properties of Maleamic Acid and Maleimide Derivatives. Journal of Solution Chemistry 2018, 47 (7) , 1269-1290.
    17. Fang-Fang Wang, Wei Yang, Yong-Hui Shi, Guo-Wei Le. In silico study on β-aminoketone derivatives as thyroid hormone receptor inhibitors: a combined 3D-QSAR and molecular docking study. Journal of Biomolecular Structure and Dynamics 2016, 81 , 1-13.
    18. Nerea Gallastegui, Eva Estébanez-Perpiñá. Thinking Outside the Box: Alternative Binding Sites in the Ligand Binding Domain of Nuclear Receptors. 2015, 179-203.
    19. Gheorghe Roman. Mannich bases in medicinal chemistry and drug design. European Journal of Medicinal Chemistry 2015, 89 , 743-816.
    20. Frank Fontaine, Jeroen Overman, Mathias François. Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles. Cell Regeneration 2015, 4 (1) , 4:2.
    21. Regina Politi, Ivan Rusyn, Alexander Tropsha. Prediction of binding affinity and efficacy of thyroid hormone receptor ligands using QSAR and structure-based modeling methods. Toxicology and Applied Pharmacology 2014, 280 (1) , 177-189.
    22. Arthur Christopoulos, Jean-Pierre Changeux, William A. Catterall, Doriano Fabbro, Thomas P. Burris, John A. Cidlowski, Richard W. Olsen, John A. Peters, Richard R. Neubig, Jean-Philippe Pin, Patrick M. Sexton, Terry P. Kenakin, Frederick J. Ehlert, Michael Spedding, Christopher J. Langmead, . International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands. Pharmacological Reviews 2014, 66 (4) , 918-947.
    23. Marcel Scheepstra, Lidia Nieto, Anna K. H. Hirsch, Sascha Fuchs, Seppe Leysen, Chan Vinh Lam, Leslie in het Panhuis, Constant A. A. van Boeckel, Hans Wienk, Rolf Boelens, Christian Ottmann, Lech‐Gustav Milroy, Luc Brunsveld. A Natural‐Product Switch for a Dynamic Protein Interface. Angewandte Chemie 2014, 126 (25) , 6561-6566.
    24. Marcel Scheepstra, Lidia Nieto, Anna K. H. Hirsch, Sascha Fuchs, Seppe Leysen, Chan Vinh Lam, Leslie in het Panhuis, Constant A. A. van Boeckel, Hans Wienk, Rolf Boelens, Christian Ottmann, Lech‐Gustav Milroy, Luc Brunsveld. A Natural‐Product Switch for a Dynamic Protein Interface. Angewandte Chemie International Edition 2014, 53 (25) , 6443-6448.
    25. Laura Caboni, David G. Lloyd. Beyond the Ligand-Binding Pocket: Targeting Alternate Sites in Nuclear Receptors. Medicinal Research Reviews 2013, 33 (5) , 1081-1118.
    26. Andreas Bernet, Marina Behr, Rodrigo Q. Albuquerque, Marko Schmidt, Jürgen Senker, Hans-Werner Schmidt. Supramolecular Chromaticity and Thermoresponsive Hydrogels: A Self-Assembly Study on Maleamic Acid-Based Amphiphiles. 2013, 1-13.
    27. Lech-Gustav Milroy, Lidia Nieto, Luc Brunsveld. Targeting alpha-helix based protein interactions; nuclear receptors as a case study. 2012, 238-272.
    28. Yuanxiang Wang, Jing Ai, Jinfeng Yue, Xia Peng, Yinchun Ji, Ailing Zhao, Xin Gao, Ying Wang, Yi Chen, Gang Liu, Zhaobing Gao, Meiyu Geng, Ao Zhang. Further SAR studies on 3,5-diamino-7-trifluoromethylquinolines as highly potent tyrosine kinase c-Met inhibitors: efforts to correct hERG inhibition. MedChemComm 2012, 3 (11) , 1423.
    29. Nuria Rodríguez, Filipe Manjolinho, Matthias F. Grünberg, Lukas J. Gooßen. Synthesis of α,β‐Unsaturated Ketones by Pd‐Catalyzed Decarboxylative Allylation of α‐Oxocarboxylates. Chemistry – A European Journal 2011, 17 (49) , 13688-13691.
    30. Ronald L. Johnson, Jong Yeon Hwang, Leggy A. Arnold, Ruili Huang, Jennifer Wichterman, Indre Augustinaite, Christopher P. Austin, James Inglese, R. Kiplin Guy, Wenwei Huang. A Quantitative High-Throughput Screen Identifies Novel Inhibitors of the Interaction of Thyroid Receptor β with a Peptide of Steroid Receptor Coactivator 2. SLAS Discovery 2011, 16 (6) , 618-627.
    31. Aiming Sun, Terry W. Moore, Jillian R. Gunther, Mi‐Sun Kim, Eric Rhoden, Yuhong Du, Haian Fu, James P. Snyder, John A. Katzenellenbogen. Discovering Small‐Molecule Estrogen Receptor α/Coactivator Binding Inhibitors: High‐Throughput Screening, Ligand Development, and Models for Enhanced Potency. ChemMedChem 2011, 6 (4) , 654-666.
    32. Jong Yeon Hwang, Wenwei Huang, Leggy A. Arnold, Ruili Huang, Ramy R. Attia, Michele Connelly, Jennifer Wichterman, Fangyi Zhu, Indre Augustinaite, Christopher P. Austin, James Inglese, Ronald L. Johnson, R. Kiplin Guy. Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone. Journal of Biological Chemistry 2011, 286 (14) , 11895-11908.
    33. A. F. Nasonov. Computational methods and software in computer-aided combinatorial library design. Russian Journal of General Chemistry 2010, 80 (12) , 2541-2571.
    34. Terry W. Moore, Christopher G. Mayne, John A. Katzenellenbogen. Minireview: Not Picking Pockets: Nuclear Receptor Alternate-Site Modulators (NRAMs). Molecular Endocrinology 2010, 24 (4) , 683-695.
    35. Lori W. Lee, Anna K. Mapp. Transcriptional Switches: Chemical Approaches to Gene Regulation. Journal of Biological Chemistry 2010, 285 (15) , 11033-11038.
    36. Eva Estébanez-Perpiñá, Robert J. Fletterick. The Androgen Receptor Coactivator-Binding Interface. 2009, 297-311.
    37. Terry W. Moore, John A. Katzenellenbogen. Chapter 21 Inhibitors of Nuclear Hormone Receptor/Coactivator Interactions. 2009, 443-457.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect