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
Summary
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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