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Developing Antagonists for the Met-HGF/SF Protein-Protein Interaction Using a Fragment-Based Approach
Anja Winter1, Anna G Sigurdardottir2, Danielle DiCara3
1Department of Molecular Cell Biology, The University of Cambridge, Cambridge, United Kingdom. aw284@le.ac.uk tom@cryst.bioc.cam.ac.uk.
Molecular Cancer Therapeutics
|December 30, 2015
Summary
Fragment-based drug discovery effectively targets the Met receptor tyrosine kinase pathway, a key driver of cancer metastasis. This approach yields novel compounds that inhibit cancer cell migration and tumor growth, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant activation of Met receptor tyrosine kinase drives cancer metastasis.
- Current Met inhibitors (kinase inhibitors, antibodies) face challenges in specificity and cost.
- Targeting the Met-HGF/SF protein-protein interaction (PPI) presents a therapeutic opportunity.
Purpose of the Study:
- To explore a fragment-based approach for targeting the Met-HGF/SF PPI.
- To identify novel small molecules inhibiting Met signaling and cancer progression.
- To develop a new class of Met receptor antagonists.
Main Methods:
- Fragment library screening using surface plasmon resonance.
- Hit compound development via substructure searches.
- In vitro assays for Met signaling, tumorsphere generation, and cell migration.
- Molecular docking for mechanism of action determination.
Main Results:
- Identified compounds that interfere with HGF/SF (NK1 fragment) binding to Met.
- Demonstrated inhibition of Met signaling, tumorsphere formation, and cell migration.
- Characterized compounds acting as direct or indirect PPI inhibitors.
Conclusions:
- Chemical fragments efficiently target the HGF/SF-Met interface.
- This strategy provides building blocks for developing biologically active lead compounds.
- Fragment-based drug discovery is a viable approach for developing novel Met inhibitors and small molecule PPI inhibitors.
