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Updated: Aug 16, 2025

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

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Protein Phosphatase 5-Recruiting Chimeras for Accelerating Apoptosis-Signal-Regulated Kinase 1 Dephosphorylation with

Qiuyue Zhang1,2, Xuexuan Wu1,2, Hengheng Zhang1,2

  • 1State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Journal of the American Chemical Society
|December 22, 2022
PubMed

Insights

Researchers developed DDO3711, a novel chimera that recruits PP5 to dephosphorylate p-ASK1(T838), effectively reducing gastric cancer progression. This targeted approach shows promise for regulating abnormally phosphorylated oncoproteins.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Aberrant protein phosphorylation, particularly hyperphosphorylation of oncoproteins like ASK1, drives cancer progression.
  • PP5 normally dephosphorylates p-ASK1(T838), but its activity is inhibited in tumors, leading to elevated p-ASK1(T838) levels.
  • Targeting protein dephosphorylation offers a strategy for cancer therapy.

Purpose of the Study:

  • To design and validate Phosphatase Recruitment Chimeras (PHORCs) for targeted dephosphorylation of p-ASK1(T838).
  • To develop a novel therapeutic strategy for gastric cancer by restoring ASK1 phosphorylation homeostasis.

Main Methods:

  • Design of DDO3711, a PHORC comprising an ASK1 inhibitor linked to a PP5 activator.
  • In vitro and in vivo experiments to assess the efficacy of DDO3711 in reducing p-ASK1(T838) levels.
  • Antiproliferative activity assays using MKN45 gastric cancer cells.

Main Results:

  • DDO3711 effectively decreased p-ASK1(T838) levels in vitro and in vivo.
  • DDO3711 demonstrated significant antiproliferative activity against MKN45 cells (IC50 = 0.5 μM) via a direct binding and proximity-mediated mechanism.
  • Neither the ASK1 inhibitor nor the PP5 activator alone or combined showed effects on MKN45 cells, highlighting the necessity of the PHORC structure.

Conclusions:

  • PHORCs, exemplified by DDO3711, are effective tools for accelerating targeted protein dephosphorylation.
  • This approach provides a novel strategy for precise phosphorylation regulation of oncoproteins.
  • The findings support the potential of PHORCs in developing new therapies for cancers driven by abnormal phosphorylation.

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