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

Abstract

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.

• Authors: Ettore J Rastelli, Sara Sannino, Duncan J Hart, Elizabeth R Sharlow, John S Lazo, Jeffrey L Brodsky, Peter Wipf
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 46 Pg. 128167 (08 15 2021) ISSN: 1464-3405 [Electronic] England
• PMID: 34089839 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Imines
• JMS-053
• Neoplasm Proteins
• Pyridines
• PTP4A3 protein, human
• Protein Tyrosine Phosphatases

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Endoplasmic Reticulum (drug effects)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Female
• Humans
• Imines (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Protein Tyrosine Phosphatases (antagonists & inhibitors, metabolism)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship