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Computational‐based discovery of FAK FERM domain chemical probes that inhibit HER2‐FAK cancer signaling by Stahl, Erik; Nott, Rohini; Koessel, Karissa; Cance, William; Marlowe, Timothy is a Chemistry article available to read on EtoBox.

What is Computational‐based discovery of FAK FERM domain chemical probes that inhibit HER2‐FAK cancer signaling about?

The N-terminal FERM domain of focal adhesion kinase (FAK) contributes to FAK scaffolding and interacts with HER2, an oncogene and receptor tyrosine kinase. The interaction between HER2 and FAK drives resistance to FAK-kinase domain inhibitors through FAK Y397 transphosphorylation and FAK re-activation upon inhibition. As such, FAK FERM remains an attractive drug discovery target. In this report, we detail an alternative approach to targeting FAK through virtual screening-based discovery of chemical probes that target FAK FERM. We validated the binding interface between HER2 and FAK using site-directed mutagenesis and GST pull-down experiments. We assessed the ligandability of key-binding residues of HER2 and FAK utilizing computational tools. We developed a virtual screening method to screen ~200,000 compounds against the FAK FERM domain, identifying 20 virtual chemical probes. We performed GST pull-down screening on these compounds, discovering two hits, VS4 and VS14, with nanomolar IC s in disrupting HER2-FAK. We performed further testing, including molecular docking, immunofluorescence, phosphorylation, and cellular invasion assays to evaluate the compounds' biological effects.

Who reads Computational‐based discovery of FAK FERM domain chemical probes that inhibit HER2‐FAK cancer signaling?

Author

Stahl, Erik; Nott, Rohini; Koessel, Karissa; Cance, William; Marlowe, Timothy

Publisher

John Wiley and Sons; Wiley (Blackwell Publishing); Blackwell; Wiley (ISSN 1747-0277)

Published

2020

Language

EN

Field

Chemistry (Physical Sciences)