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PTGES3 proteolysis using the liposomal peptide-PROTAC approach.

Shiwei Liu¹, Fukang Yuan^2,3, Hui Dong⁴

¹School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China.

|December 26, 2024

Summary

Researchers developed novel peptide PROTACs (p-PROTACs) to degrade Prostaglandin E Synthase 3 (PTGES3) in hepatocellular carcinoma (HCC). This targeted protein degradation approach shows promise for treating HCC by weakening the cancer's malignant phenotype.

Keywords:

Hepatocellular Carcinoma Liposome PTGES3 Peptide proteolysis-targeting chimera

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Area of Science:

Oncology
Molecular Biology
Drug Discovery

Background:

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally, with limited early detection biomarkers.
Prostaglandin E Synthase 3 (PTGES3) expression and function in HCC remain largely uncharacterized.
Proteolysis-targeting chimera (PROTAC) technology offers a novel approach for targeted protein degradation, including for previously undruggable targets.

Purpose of the Study:

To investigate the role of PTGES3 in HCC.
To develop and evaluate PTGES3-targeting peptide PROTACs (p-PROTACs) for HCC therapy.
To assess the efficacy of PTGES3 degradation in reducing HCC malignancy.

Main Methods:

Developed PTGES3-PROTACs incorporating a PTGES3-binding peptide and pomalidomide.
Optimized ligand ratios for enhanced degradation efficacy.
Evaluated PTGES3 protein levels and HCC cell behavior in vitro and in vivo.

Main Results:

PTGES3 is significantly overexpressed in HCC at both transcriptional and protein levels.
PTGES3-PROTACs effectively degraded PTGES3 protein.
Degradation of PTGES3 significantly attenuated the malignant phenotype of HCC cells in vitro and in vivo.

Conclusions:

Targeted PTGES3 proteolysis represents a viable therapeutic strategy for HCC.
PTGES3-PROTACs demonstrate potential as safe and effective therapeutic agents for HCC treatment.