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Discovery of SZJK-0421: A Novel Potent, Low Toxicity, Selective Second Generation of CRM1 Inhibitor for the Treatment of Both Hematological and Solid Tumors

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2024, 67, 22, 20595-20618
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    Discovery of SZJK-0421: A Novel Potent, Low Toxicity, Selective Second Generation of CRM1 Inhibitor for the Treatment of Both Hematological and Solid Tumors
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    • Hang Miao
      Hang Miao
      College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, P. R. China
      More by Hang Miao
      Orcidhttps://orcid.org/0009-0000-4132-3795
    • Yanru Qin
      Yanru Qin
      College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, P. R. China
      More by Yanru Qin
    • DingLu Shao
      DingLu Shao
      College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, P. R. China
      More by DingLu Shao
    • Qinghua Chen
      Qinghua Chen
      College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, P. R. China
      More by Qinghua Chen
    • Yupeng Pan
      Yupeng Pan
      College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, P. R. China
      More by Yupeng Pan
    • Meng Lei
      Meng Lei
      College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, P. R. China
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    • Ruokun Wu
      Ruokun Wu
      College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, P. R. China
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    • Xinran Ye
      Xinran Ye
      College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, P. R. China
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    • Xueyuan Wang*
      Xueyuan Wang
      College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, P. R. China
      *Email: [email protected]
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    • Yongqiang Zhu*
      Yongqiang Zhu
      College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, P. R. China
      *Email: [email protected]
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    Other Access OptionsSupporting Information (4)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 22, 20595–20618
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    https://doi.org/10.1021/acs.jmedchem.4c02169
    Published November 7, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    Nuclear export factor chromosome region maintenance 1 (CRM1) mediated the transport of various growth-regulatory proteins and was frequently overexpressed in many hematologic and solid tumors. Selinexor (KPT-330) was the only approved CRM1 inhibitor, but the severe gastrointestinal and central nervous system toxicities limited its clinical application. In this manuscript, a series of novel second-generation CRM1 inhibitors were designed, in which SZJK-0421 was a more reversible inhibitor than KPT-330. The treatment of various tumor cells with SZJK-0421 significantly inhibited the function of CRM1. SZJK-0421 displayed good liver microsome stabilities and pharmacokinetic properties. Most importantly, SZJK-0421 reduced the direct damage to the gastrointestinal mucosa, and the brain plasma distribution ratio of SZJK-0421 was very low in Sprague-Dawley (SD) rats (3%), which avoided gastrointestinal reactions such as central nausea and vomiting caused by large permeability of blood–brain barrier. In addition, SZJK-0421 exhibited strong anticancer efficacy in xenograft models of both solid and hematological tumors.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02169.

    • Nostandard abbreviations and acronyms (PDF)

    • Crystallographic data (PDB)

    • Synthetic route of compound Biotin-0421, NMR spectra of all target compounds, HPLC spectra of compound SZJK-0421, and the effect of compound SZJK-0421 on forelimb grip strength in SD rats (PDF)

    • Molecular formula strings (CSV)

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 22, 20595–20618
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.4c02169
    Published November 7, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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