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Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2022, 65, 12, 8303-8331
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    Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis
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    • Kevin J. Frankowski*
      Kevin J. Frankowski
      KU Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States
      Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
      *Email: [email protected]
      More by Kevin J. Frankowski
      Orcidhttps://orcid.org/0000-0002-7173-6352
    • Samarjit Patnaik*
      Samarjit Patnaik
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      *Email: [email protected]
      More by Samarjit Patnaik
      Orcidhttps://orcid.org/0000-0002-4265-7620
    • Chen Wang
      Chen Wang
      Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611, United States
      More by Chen Wang
    • Noel Southall
      Noel Southall
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Noel Southall
      Orcidhttps://orcid.org/0000-0003-4500-880X
    • Dipannita Dutta
      Dipannita Dutta
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Dipannita Dutta
    • Soumitta De
      Soumitta De
      Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, United States
      More by Soumitta De
    • Dandan Li
      Dandan Li
      Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, United States
      More by Dandan Li
    • Christopher Dextras
      Christopher Dextras
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Christopher Dextras
    • Yi-Han Lin
      Yi-Han Lin
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Yi-Han Lin
    • Marthe Bryant-Connah
      Marthe Bryant-Connah
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Marthe Bryant-Connah
    • Danielle Davis
      Danielle Davis
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Danielle Davis
    • Feijun Wang
      Feijun Wang
      Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
      More by Feijun Wang
    • Leah M. Wachsmuth
      Leah M. Wachsmuth
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Leah M. Wachsmuth
    • Pranav Shah
      Pranav Shah
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Pranav Shah
    • Jordan Williams
      Jordan Williams
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Jordan Williams
    • Md Kabir
      Md Kabir
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Md Kabir
    • Edward Zhu
      Edward Zhu
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Edward Zhu
    • Bolormaa Baljinnyam
      Bolormaa Baljinnyam
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Bolormaa Baljinnyam
    • Amy Wang
      Amy Wang
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Amy Wang
    • Xin Xu
      Xin Xu
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Xin Xu
    • John Norton
      John Norton
      Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611, United States
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    • Marc Ferrer
      Marc Ferrer
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Marc Ferrer
    • Steve Titus
      Steve Titus
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Steve Titus
    • Anton Simeonov
      Anton Simeonov
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Anton Simeonov
    • Wei Zheng
      Wei Zheng
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Wei Zheng
    • Lesley A. Mathews Griner
      Lesley A. Mathews Griner
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Lesley A. Mathews Griner
    • Ajit Jadhav
      Ajit Jadhav
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Ajit Jadhav
    • Jeffrey Aubé
      Jeffrey Aubé
      KU Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States
      Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
      More by Jeffrey Aubé
      Orcidhttps://orcid.org/0000-0003-1049-5767
    • Mark J. Henderson
      Mark J. Henderson
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      More by Mark J. Henderson
      Orcidhttps://orcid.org/0000-0001-8590-7338
    • Udo Rudloff
      Udo Rudloff
      Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, United States
      More by Udo Rudloff
    • Frank J. Schoenen
      Frank J. Schoenen
      KU Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States
      More by Frank J. Schoenen
    • Sui Huang*
      Sui Huang
      Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611, United States
      *Email: [email protected]
      More by Sui Huang
    • Juan J. Marugan*
      Juan J. Marugan
      National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
      *Email: [email protected]
      More by Juan J. Marugan
      Orcidhttps://orcid.org/0000-0002-3951-7061
    Other Access OptionsSupporting Information (2)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 12, 8303–8331
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    https://doi.org/10.1021/acs.jmedchem.2c00204
    Published June 13, 2022
    Copyright © 2022 American Chemical Society
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    Abstract

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    The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. Structure–activity relationship exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of in vitro drug-like properties led to the discovery of the bioavailable analogue, metarrestin, which has shown potent antimetastatic activity with improved survival in rodent models and is currently being evaluated in a first-in-human phase 1 clinical trial.

    Copyright © 2022 American Chemical Society

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    This article is cited by 9 publications.

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    2. Eugene V. Makeyev, Sui Huang. The perinucleolar compartment: structure, function, and utility in anti-cancer drug development. Nucleus 2024, 15 (1) https://doi.org/10.1080/19491034.2024.2306777
    3. Aleksandra Sochacka-Ćwikła, Andrzej Regiec, Żaneta Czyżnikowska, Urszula Śliwińska-Hill, Anna Kwiecień, Benita Wiatrak, Agnieszka Rusak, Klaudia Krawczyńska, Monika Mrozowska, Sylwia Borska, Katarzyna Ratajczak, Anna Pyra, Marcin Mączyński. Synthesis and structural proof of novel oxazolo[5,4-d]pyrimidine derivatives as potential VEGFR2 inhibitors. In vitro study of their anticancer activity. Bioorganic Chemistry 2024, 153 , 107958. https://doi.org/10.1016/j.bioorg.2024.107958
    4. Vivek K. Kashyap, Bhuvnesh P. Sharma, Divya Pandey, Ajay K. Singh, Godwin Peasah-Darkwah, Bhupesh Singh, Kuldeep K. Roy, Murali M. Yallapu, Subhash C. Chauhan. Small Molecule with Big Impact: Metarrestin Targets the Perinucleolar Compartment in Cancer Metastasis. Cells 2024, 13 (24) , 2053. https://doi.org/10.3390/cells13242053
    5. Carl C. Correll, Udo Rudloff, Jeremy D. Schmit, David A. Ball, Tatiana S. Karpova, Eric Balzer, Miroslav Dundr. Crossing boundaries of light microscopy resolution discerns novel assemblies in the nucleolus. Histochemistry and Cell Biology 2024, 162 (1-2) , 161-183. https://doi.org/10.1007/s00418-024-02297-7
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    9. Jessica M. Faupel‐Badger, Amanda L. Vogel, Christopher P. Austin, Joni L. Rutter. Advancing translational science education. Clinical and Translational Science 2022, 15 (11) , 2555-2566. https://doi.org/10.1111/cts.13390
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 12, 8303–8331
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.2c00204
    Published June 13, 2022
    Copyright © 2022 American Chemical Society
    Request reuse permissions

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