Identification of potential small-molecule protein-protein inhibitors of cancer metastasis by 3D epitope-based...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Extracellular pressure and shear stress activate AKT1-FAK interaction in cancer cells, promoting metastasis.
• Targeting the AKT1-FAK interaction offers a therapeutic strategy to inhibit cancer cell adhesion and metastasis.
• Global FAK inhibition can cause side effects, necessitating targeted approaches.

Purpose of the Study:

• To identify small-molecule inhibitors that specifically block the AKT1-FAK interaction.
• To develop a novel method for inhibiting protein-protein interactions using 3D structural queries.
• To evaluate the efficacy of identified compounds in reducing pressure-induced FAK phosphorylation in colon cancer cells.

Main Methods:

• Utilized a previously identified FAK peptide that binds AKT1 as a starting point.
• Employed a novel ligand-based virtual screening approach using a 3D structural fragment of the FAK peptide as a query.
• Screened millions of commercially available drug-like molecules for those mimicking the FAK fragment's volume and chemistry.
• Tested candidate compounds for their ability to inhibit pressure-sensitive FAK phosphorylation by AKT1 in SW620 colon cancer cells.

Main Results:

• Two small-molecule compounds were identified that effectively reduced stimulated FAK phosphorylation in response to extracellular pressure.
• These compounds did not affect basal FAK phosphorylation levels.
• The study successfully demonstrated the utility of 3D protein interaction epitopes in virtual screening.

Conclusions:

• A novel 3D epitope-based virtual screening approach can identify small molecules targeting protein-protein interactions.
• The identified compounds show promise for modulating cancer cell adhesion and metastasis.
• This targeted inhibition strategy may offer a safer alternative to global FAK inhibition in cancer therapy.