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ORIGINAL RESEARCH article

Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 12 - 2024 | doi: 10.3389/fchem.2024.1381205
This article is part of the Research Topic Spotlight on North America - Chemical Sciences View all 7 articles

Stretching the structural envelope of imatinib to reduce β-amyloid production by modulating both β-and γ-secretase cleavages of APP

Provisionally accepted
William J. Netzer William J. Netzer 1*Anjana Sinha Anjana Sinha 1*Mondana Ghias Mondana Ghias 1*Emily Chang Emily Chang 1Katherina Gindinova Katherina Gindinova 1*Emily Mui Emily Mui 1*Ji-Seon Seo Ji-Seon Seo 1Subhash C. Sinha Subhash C. Sinha 1,2*
  • 1 The Rockefeller University, New York City, New York, United States
  • 2 Weill Cornell Medicine, Cornell University, New York, New York, United States

The final, formatted version of the article will be published soon.

    We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103.In the present study, we synthesized and tested radically altered IMT isomers (IMTi's) that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization.

    Keywords: Imatinib (IMT) or Gleevec, DV2-103, Gamma secretase, inhibitor, modulator, ab, isomer

    Received: 03 Feb 2024; Accepted: 10 Sep 2024.

    Copyright: © 2024 Netzer, Sinha, Ghias, Chang, Gindinova, Mui, Seo and Sinha. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    William J. Netzer, The Rockefeller University, New York City, 10065, New York, United States
    Anjana Sinha, The Rockefeller University, New York City, 10065, New York, United States
    Mondana Ghias, The Rockefeller University, New York City, 10065, New York, United States
    Katherina Gindinova, The Rockefeller University, New York City, 10065, New York, United States
    Emily Mui, The Rockefeller University, New York City, 10065, New York, United States
    Subhash C. Sinha, Weill Cornell Medicine, Cornell University, New York, 10065, New York, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.