Fragment-based drug design targeting syntenin PDZ2 domain involved in exosomal release and tumour spread

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Syntenin is upregulated in cancers, promoting tumor metastasis via exosome production.
• Syntenin's PDZ domains interact with syndecans, mediating these pro-metastatic effects.

Purpose of the Study:

• To develop novel inhibitors targeting the syntenin-syndecan interaction using fragment-based drug design.
• To identify small molecules that selectively inhibit syntenin-mediated exosome release.

Main Methods:

• Fragment-based drug design and in vitro screening of a PDZ-focused library.
• X-ray crystallography and computational docking to guide inhibitor optimization.
• Biochemical assays to evaluate inhibition of syntenin-syndecan interaction and exosome release.

Main Results:

• A fragment hit (C58) was identified, binding specifically to the syntenin-PDZ2 domain.
• Optimization led to compounds 45 and 57, potent inhibitors of syntenin-syndecan interaction (IC50 = 33 μM and 47 μM).
• These compounds selectively inhibited syntenin-exosome release.

Conclusions:

• Small molecules can effectively inhibit syntenin-syndecan interactions.
• Inhibiting syntenin-mediated exosome release is a viable strategy for cancer therapy.
• Developed inhibitors show potential for treating metastatic cancers.