| Title: |
A Discovery Strategy for Selective Inhibitors of c‐Src in Complex with the Focal Adhesion Kinase SH3/SH2‐binding Region |
| Authors: |
Moroco, Jamie A.; Baumgartner, Matthew P.; Rust, Heather L.; Choi, Hwan Geun; Hur, Wooyoung; Gray, Nathanael S.; Camacho, Carlos J.; Smithgall, Thomas E. |
| Contributors: |
National Institutes of Health; NIH |
| Source: |
Chemical Biology & Drug Design ; volume 86, issue 2, page 144-155 ; ISSN 1747-0277 1747-0285 |
| Publisher Information: |
Wiley |
| Publication Year: |
2014 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
The c‐Src tyrosine kinase co‐operates with the focal adhesion kinase to regulate cell adhesion and motility. Focal adhesion kinase engages the regulatory SH3 and SH2 domains of c‐Src, resulting in localized kinase activation that contributes to tumor cell metastasis. Using assay conditions where c‐Src kinase activity required binding to a tyrosine phosphopeptide based on the focal adhesion kinase SH3‐SH2 docking sequence, we screened a kinase‐biased library for selective inhibitors of the Src/focal adhesion kinase peptide complex versus c‐Src alone. This approach identified an aminopyrimidinyl carbamate compound, WH‐4‐124‐2, with nanomolar inhibitory potency and fivefold selectivity for c‐Src when bound to the phospho‐focal adhesion kinase peptide. Molecular docking studies indicate that WH‐4‐124‐2 may preferentially inhibit the ‘DFG‐out’ conformation of the kinase active site. These findings suggest that interaction of c‐Src with focal adhesion kinase induces a unique kinase domain conformation amenable to selective inhibition. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1111/cbdd.12473 |
| Availability: |
https://doi.org/10.1111/cbdd.12473; https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fcbdd.12473; https://onlinelibrary.wiley.com/doi/pdf/10.1111/cbdd.12473 |
| Rights: |
http://onlinelibrary.wiley.com/termsAndConditions#vor |
| Accession Number: |
edsbas.ECD9AC5E |
| Database: |
BASE |