Fragment Based Drug Discovery of Allosteric FAK Inhibitors

Undergraduate #4
Discipline: Biological Sciences
Subcategory: Cancer Research

Osvaldo Cossio - University of Arkansas at Little Rock
Co-Author(s): Ramon Campos-Olivas, Clara Santiveri, Daniel Lietha, and Marta Acebron, Spanish National Cancer Research Centre (CNIO), Madrid Spain

---

The Focal Adhesion Kinase (FAK) is a cytoplasmic tyrosine kinase that plays a key role in cell matrix adhesion signals. Here, signaling is essential for cell migration and proliferation. In several advanced-stage solid cancers, FAK is overexpressed and helps to promote tumor invasion and metastasis. This discovery has led to much research on developing small molecule FAK inhibitors that target the FAK Kinase Domain ATP binding site. However, due to the similarity of ATP binding sites between different kinases this raises concern on the undesired toxicities that could result. Therefore, our research focuses on finding allosteric small molecule FAK inhibitors that target the kinase function but not the active ATP-binding site. To find novel allosteric small molecule FAK inhibitors, we employed the fragment-based drug discovery approach. A collection of about 500 fluorinated small molecules was screened against the FAK protein target with 1D 19F Nuclear Magnetic Resonance (NMR). To identify the binding between small molecules and FAK protein targets, the increase in the small molecules 19F NMR signal linewidth was used. The hits identified in our research represent potential fragments that can be used to further develop them into lead compounds possessing drug-like properties against this protein overexpressed in cancer. Our future studies will involve further characterizing the hits with WaterLOGSY (WL) and saturation transfer difference (STD) NMR experiments, SPR analysis, and crystallography.

Funder Acknowledgement(s): Spanish National Cancer Research Centre (CNIO)

Faculty Advisor: Janet Lanza,