Synthesis and evaluation of bifunctional PTP4A3 phosphatase inhibitors activating the ER stress pathway.

Autor: Rastelli EJ; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States., Sannino S; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States., Hart DJ; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, United States., Sharlow ER; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, United States., Lazo JS; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, United States., Brodsky JL; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States., Wipf P; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States. Electronic address: pwipf@pitt.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Aug 15; Vol. 46, pp. 128167. Date of Electronic Publication: 2021 Jun 02.
DOI: 10.1016/j.bmcl.2021.128167
Abstrakt: We developed JMS-053, a potent inhibitor of the dual specificity phosphatase PTP4A3 that is potentially suitable for cancer therapy. Due to the emerging role of the unfolded protein response (UPR) in cancer pathology, we sought to identify derivatives that combine PTP4A3 inhibition with induction of endoplasmatic reticulum (ER) stress, with the goal to generate more potent anticancer agents. We have now generated bifunctional analogs that link the JMS-053 pharmacophore to an adamantyl moiety and act in concert with the phosphatase inhibitor to induce ER stress and cell death. The most potent compound in this series, 7a, demonstrated a ca. 5-fold increase in cytotoxicity in a breast cancer cell line and strong activation of UPR and ER stress response genes in spite of a ca. 13-fold decrease in PTP4A3 inhibition. These results demonstrate that the combination of phosphatase inhibition with UPR/ER-stress upregulation potentiates efficacy.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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