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Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5)

  • Rachel L. Palte*
    Rachel L. Palte
    Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
    *Email: [email protected]
  • Sebastian E. Schneider*
    Sebastian E. Schneider
    Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
    *Email: [email protected]
  • Michael D. Altman
    Michael D. Altman
    Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
  • Robert P. Hayes
    Robert P. Hayes
    Computational and Structural Chemistry, West Point, Pennsylvania 19486, United States
  • Shuhei Kawamura
    Shuhei Kawamura
    Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
  • Brian M. Lacey
    Brian M. Lacey
    Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
  • My Sam Mansueto
    My Sam Mansueto
    Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
  • Michael Reutershan
    Michael Reutershan
    Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
  • Phieng Siliphaivanh
    Phieng Siliphaivanh
    Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
  • Christopher Sondey
    Christopher Sondey
    Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
  • Haiyan Xu
    Haiyan Xu
    Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
    More by Haiyan Xu
  • Zangwei Xu
    Zangwei Xu
    Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
    More by Zangwei Xu
  • Yingchun Ye
    Yingchun Ye
    Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
    More by Yingchun Ye
  • , and 
  • Michelle R. Machacek
    Michelle R. Machacek
    Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
Cite this: ACS Med. Chem. Lett. 2020, 11, 9, 1688–1693
Publication Date (Web):August 7, 2020
https://doi.org/10.1021/acsmedchemlett.9b00525
Copyright © 2020 American Chemical Society

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Abstract

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Protein arginine methyltransferase 5 (PRMT5) belongs to a family of enzymes that regulate the posttranslational modification of histones and other proteins via methylation of arginine. Methylation of histones is linked to an increase in transcription and regulates a manifold of functions such as signal transduction and transcriptional regulation. PRMT5 has been shown to be upregulated in the tumor environment of several cancer types, and the inhibition of PRMT5 activity was identified as a potential way to reduce tumor growth. Previously, four different modes of PRMT5 inhibition were known—competing (covalently or non-covalently) with the essential cofactor S-adenosyl methionine (SAM), blocking the substrate binding pocket, or blocking both simultaneously. Herein we describe an unprecedented conformation of PRMT5 in which the formation of an allosteric binding pocket abrogates the enzyme’s canonical binding site and present the discovery of potent small molecule allosteric PRMT5 inhibitors.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00525.

  • Experimental procedures for the biochemical assay, cell-based assay, SPR studies, chemical syntheses, NMR and ECD studies for the determination of absolute stereochemistry, protein expression and purifications, and X-ray crystallography. Also included is the crystallography data collection and refinement statistics, PRMT loop comparisons, and SPR raw data. (PDF)

Accession Codes

Compound 1a, 6UXX; compound 8, 6UXY.

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Cited By

This article is cited by 24 publications.

  1. Deqin Rong, Kaixin Zhou, Wei Fang, Hong Yang, Yi Zhang, Qiongyu Shi, Yuting Huang, Jiayi Li, Hui Dong, Lanlan Li, Jian Ding, Xun Huang, Yuanxiang Wang. Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5. Journal of Medicinal Chemistry 2022, 65 (11) , 7854-7875. https://doi.org/10.1021/acs.jmedchem.2c00398
  2. Ryan V. Quiroz, Michael H. Reutershan, Sebastian E. Schneider, David Sloman, Brian M. Lacey, Brooke M. Swalm, Charles S. Yeung, Craig Gibeau, Daniel S. Spellman, Danica A. Rankic, Dapeng Chen, David Witter, Doug Linn, Erik Munsell, Guo Feng, Haiyan Xu, Jonathan M. E. Hughes, Jongwon Lim, Josep Saurí, Kristin Geddes, Murray Wan, My Sam Mansueto, Nicole E. Follmer, Patrick S. Fier, Phieng Siliphaivanh, Pierre Daublain, Rachel L. Palte, Robert P. Hayes, Sandra Lee, Shuhei Kawamura, Steven Silverman, Sulagna Sanyal, Timothy J. Henderson, Yingchun Ye, Yuanwei Gao, Benjamin Nicholson, Michelle R. Machacek. The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer. Journal of Medicinal Chemistry 2021, 64 (7) , 3911-3939. https://doi.org/10.1021/acs.jmedchem.0c02083
  3. Yudao Shen, Fengling Li, Magdalena M. Szewczyk, Levon Halabelian, Irene Chau, Mohammad S. Eram, Carlo Dela Seña, Kwang-Su Park, Fanye Meng, He Chen, Hong Zeng, Aiping Dong, Hong Wu, Viacheslav V. Trush, David McLeod, Carlos A. Zepeda-Velázquez, Robert M. Campbell, Mary M. Mader, Brian M. Watson, Matthieu Schapira, Cheryl H. Arrowsmith, Rima Al-Awar, Dalia Barsyte-Lovejoy, H. Ümit Kaniskan, Peter J. Brown, Masoud Vedadi, Jian Jin. A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6. Journal of Medicinal Chemistry 2021, 64 (7) , 3697-3706. https://doi.org/10.1021/acs.jmedchem.0c02160
  4. Bing Xiong. Allosteric Modulation: Dynamics is Double-“E”dged. Journal of Medicinal Chemistry 2021, 64 (7) , 3694-3696. https://doi.org/10.1021/acs.jmedchem.1c00473
  5. Stuart J. Conway, (Associate Editor, Journal of Medicinal Chemistry)Paola Arimondo, (Guest Editor, Institut Pasteur Paris)Cheryl Arrowsmith, (Guest Editor, University of Toronto)Jian Jin, (Guest Editor, Icahn School of Medicine at Mount Sinai)Cheng Luo, (Guest Editor, Shanghai Institute of Materia Medica)Nicholas Meanwell, (Perspectives Editor, Journal of Medicinal Chemistry)Wendy Young, (Drug Annotations Editor, Journal of Medicinal Chemistry)Gunda Georg, (Editor-in-Chief, Journal of Medicinal Chemistry)Shaomeng Wang (Editor-in-Chief, Journal of Medicinal Chemistry). Epigenetics 2.0: Special Issue on Epigenetics—Call for Papers. Journal of Medicinal Chemistry 2020, 63 (21) , 12129-12130. https://doi.org/10.1021/acs.jmedchem.0c01748
  6. Limin Zhang, Huihui Wang, Weimin Li. PRMT5 up-regulation improves myocardial hypertrophy by mediating E2F-1/NF-κB/NLRP3 pathway. Preventive Medicine 2023, 172 , 107553. https://doi.org/10.1016/j.ypmed.2023.107553
  7. Rajiv Gandhi Govindaraj, Sundar Thangapandian, Michael Schauperl, Rajiah Aldrin Denny, David J. Diller. Recent applications of computational methods to allosteric drug discovery. Frontiers in Molecular Biosciences 2023, 9 https://doi.org/10.3389/fmolb.2022.1070328
  8. Amar Pratap Singh, Rakesh Kumar, Dinesh Gupta. Structural insights into the mechanism of human methyltransferase hPRMT4. Journal of Biomolecular Structure and Dynamics 2022, 40 (21) , 10821-10834. https://doi.org/10.1080/07391102.2021.1950567
  9. Wei Zhou, Gaya P. Yadav, Xiaozhi Yang, Feng Qin, Chenglong Li, Qiu-Xing Jiang. Cryo-EM structure-based selection of computed ligand poses enables design of MTA-synergic PRMT5 inhibitors of better potency. Communications Biology 2022, 5 (1) https://doi.org/10.1038/s42003-022-03991-9
  10. Benjamin McLean, Aji Istadi, Teleri Clack, Mezzalina Vankan, Daniel Schramek, G. Gregory Neely, Marina Pajic. A CRISPR Path to Finding Vulnerabilities and Solving Drug Resistance: Targeting the Diverse Cancer Landscape and Its Ecosystem. Advanced Genetics 2022, 3 (4) , 2200014. https://doi.org/10.1002/ggn2.202200014
  11. Siyu Fu, Qinwen Zheng, Dan Zhang, Congcong Lin, Liang Ouyang, Jifa Zhang, Lei Chen. Medicinal chemistry strategies targeting PRMT5 for cancer therapy. European Journal of Medicinal Chemistry 2022, 244 , 114842. https://doi.org/10.1016/j.ejmech.2022.114842
  12. Rita Börzsei, Bayartsetseg Bayarsaikhan, Balázs Zoltán Zsidó, Beáta Lontay, Csaba Hetényi. The Structural Effects of Phosphorylation of Protein Arginine Methyltransferase 5 on Its Binding to Histone H4. International Journal of Molecular Sciences 2022, 23 (19) , 11316. https://doi.org/10.3390/ijms231911316
  13. Yixuan Tang, Shihui Huang, Xingxing Chen, Junzhang Huang, Qianwen Lin, Lei Huang, Shuping Wang, Qihua Zhu, Yungen Xu, Yi Zou. Design, Synthesis and Biological Evaluation of Novel and Potent Protein Arginine Methyltransferases 5 Inhibitors for Cancer Therapy. Molecules 2022, 27 (19) , 6637. https://doi.org/10.3390/molecules27196637
  14. Xinyu Bai, Zheng Zhai, Xuyang Zhao, Ridong Li, Ling Liang, Yan Jin, Yuxin Yin. Discovery of novel PRMT5 inhibitors bearing a methylpiperazinyl moiety. Future Medicinal Chemistry 2022, 14 (14) , 1071-1086. https://doi.org/10.4155/fmc-2021-0244
  15. Ziyan Yang, Tian Xiao, Zezhi Li, Jian Zhang, Suning Chen. Novel Chemicals Derived from Tadalafil Exhibit PRMT5 Inhibition and Promising Activities against Breast Cancer. International Journal of Molecular Sciences 2022, 23 (9) , 4806. https://doi.org/10.3390/ijms23094806
  16. Yingqing Chen, Xiaomin Shao, Xiangge Zhao, Yuan Ji, Xiaorong Liu, Peixuan Li, Mingyu Zhang, Qianqian Wang. Targeting protein arginine methyltransferase 5 in cancers: Roles, inhibitors and mechanisms. Biomedicine & Pharmacotherapy 2021, 144 , 112252. https://doi.org/10.1016/j.biopha.2021.112252
  17. Dirk Brehmer, Lijs Beke, Tongfei Wu, Hillary J. Millar, Christopher Moy, Weimei Sun, Geert Mannens, Vineet Pande, An Boeckx, Erika van Heerde, Thomas Nys, Emmanuel M. Gustin, Bie Verbist, Longen Zhou, Yue Fan, Vipul Bhargava, Pegah Safabakhsh, Petra Vinken, Tinne Verhulst, Angelique Gilbert, Sumit Rai, Timothy A. Graubert, Friederike Pastore, Danilo Fiore, Junchen Gu, Amy Johnson, Ulrike Philippar, Barbara Morschhäuser, David Walker, Desiree De Lange, Vikki Keersmaekers, Marcel Viellevoye, Gaston Diels, Wim Schepens, Jan Willem Thuring, Lieven Meerpoel, Kathryn Packman, Matthew V. Lorenzi, Sylvie Laquerre. Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity. Molecular Cancer Therapeutics 2021, 20 (12) , 2317-2328. https://doi.org/10.1158/1535-7163.MCT-21-0367
  18. Michael K. C. Lee, Sean M. Grimmond, Grant A. McArthur, Karen E. Sheppard. PRMT5: An Emerging Target for Pancreatic Adenocarcinoma. Cancers 2021, 13 (20) , 5136. https://doi.org/10.3390/cancers13205136
  19. Zehui Tan, Tong Li, Hongrui Lei, Xin Zhai. An update on allosteric modulators as a promising strategy targeting histone methyltransferase. Pharmacological Research 2021, 172 , 105865. https://doi.org/10.1016/j.phrs.2021.105865
  20. Ernesto Guccione, Megan Schwarz, Federico Di Tullio, Slim Mzoughi. Cancer synthetic vulnerabilities to protein arginine methyltransferase inhibitors. Current Opinion in Pharmacology 2021, 59 , 33-42. https://doi.org/10.1016/j.coph.2021.04.004
  21. Qin Wu, Matthieu Schapira, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy. Protein arginine methylation: from enigmatic functions to therapeutic targeting. Nature Reviews Drug Discovery 2021, 20 (7) , 509-530. https://doi.org/10.1038/s41573-021-00159-8
  22. Iredia D. Iyamu, Ayad A. Al-Hamashi, Rong Huang. A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes. Biomolecules 2021, 11 (6) , 854. https://doi.org/10.3390/biom11060854
  23. Sabrina F. Samuel, Antonia Barry, John Greenman, Pedro Beltran-Alvarez. Arginine methylation: the promise of a ‘silver bullet’ for brain tumours?. Amino Acids 2021, 53 (4) , 489-506. https://doi.org/10.1007/s00726-020-02937-x
  24. Tanner Wright, Yalong Wang, Mark T. Bedford. The Role of the PRMT5–SND1 Axis in Hepatocellular Carcinoma. Epigenomes 2021, 5 (1) , 2. https://doi.org/10.3390/epigenomes5010002

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