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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- 1 The Rockefeller University, New York City, New York, United States
- 2 Weill Cornell Medicine, Cornell University, New York, New York, United States
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
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