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

Ettore J Rastelli1, Sara Sannino2, Duncan J Hart3

  • 1Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States.

Bioorganic & Medicinal Chemistry Letters
|June 5, 2021
PubMed

Insights

Researchers developed a new bifunctional compound that inhibits PTP4A3 phosphatase and induces endoplasmic reticulum (ER) stress. This dual action enhances cancer cell killing, showing promise for novel cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The dual specificity phosphatase PTP4A3 plays a role in cancer pathology.
  • The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress are increasingly recognized as significant factors in cancer development and progression.
  • Targeting these pathways offers potential for novel cancer therapeutic strategies.

Purpose of the Study:

  • To develop novel bifunctional anticancer agents by combining PTP4A3 inhibition with the induction of ER stress.
  • To create derivatives of JMS-053 that exhibit enhanced cytotoxicity against cancer cells.

Main Methods:

  • Synthesis of bifunctional analogs linking the JMS-053 pharmacophore to an adamantyl moiety.
  • Evaluation of cytotoxicity in breast cancer cell lines.
  • Assessment of UPR and ER stress gene activation.

Main Results:

  • Compound 7a, a potent bifunctional analog, significantly increased cytotoxicity in a breast cancer cell line (approx. 5-fold).
  • Compound 7a strongly activated UPR and ER stress response genes.
  • This enhanced efficacy was observed despite a reduced inhibitory effect on PTP4A3 (approx. 13-fold decrease).

Conclusions:

  • The combination of PTP4A3 phosphatase inhibition and UPR/ER-stress upregulation potentiates anticancer efficacy.
  • Bifunctional molecules targeting both pathways represent a promising strategy for developing more effective cancer therapies.
Keywords:
Cancer cell deathChaperonesDual-pathway agentsEndoplasmatic reticulum stressPTP4A phosphatase

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