A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Aggressive cancers like glioblastoma (GBM) have poor prognoses despite therapeutic advances.
• The intracellular scaffold protein syntenin, with its PDZ domains, is a potential therapeutic target in malignant tumors.
• Targeting syntenin offers a novel strategy for developing new glioblastoma treatments.

Purpose of the Study:

• To develop a potent and metabolically stable peptide inhibitor of syntenin.
• To evaluate the therapeutic potential of the novel inhibitor KSL-128114 against glioblastoma.

Main Methods:

• Designed and synthesized KSL-128114, a peptide inhibitor targeting syntenin's PDZ1 domain.
• Assessed KSL-128114's binding affinity, metabolic stability, and selectivity.
• Determined the X-ray crystal structure of KSL-128114 bound to syntenin PDZ1.
• Evaluated KSL-128114's efficacy in inhibiting primary GBM cell viability and in a patient-derived xenograft mouse model.

Main Results:

• KSL-128114 demonstrated nanomolar affinity for the syntenin PDZ1 domain.
• The peptide inhibitor exhibited resistance to degradation in human plasma and mouse hepatic microsomes.
• X-ray crystallography revealed a noncanonical binding mode of KSL-128114 to syntenin PDZ1.
• KSL-128114 inhibited GBM cell viability and significantly extended survival in a preclinical mouse model.

Conclusions:

• KSL-128114 is a potent, selective, and metabolically stable peptide inhibitor of syntenin.
• KSL-128114 exhibits therapeutic potential for treating aggressive cancers, including glioblastoma.
• This novel inhibitor represents a promising candidate for further clinical development against highly malignant tumors.