Format

Send to

Choose Destination
Bioorg Med Chem Lett. 2013 Oct 1;23(19):5401-9. doi: 10.1016/j.bmcl.2013.07.050. Epub 2013 Jul 31.

Fragment-based discovery of focal adhesion kinase inhibitors.

Author information

1
Merck KGaA, Merck Serono Research, Darmstadt, Germany. ulrich.graedler@merckgroup.com

Abstract

Chemically diverse fragment hits of focal adhesion kinase (FAK) were discovered by surface plasmon resonance (SPR) screening of our in-house fragment library. Site specific binding of the primary hits was confirmed in a competition setup using a high-affinity ATP-site inhibitor of FAK. Protein crystallography revealed the binding mode of 41 out of 48 selected fragment hits within the ATP-site. Structural comparison of the fragment binding modes with a DFG-out inhibitor of FAK initiated first synthetic follow-up optimization leading to improved binding affinity.

KEYWORDS:

DFG-out; Focal adhesion kinase; Fragment screening; Surface plasmon resonance; X-ray structure

PMID:
23973211
DOI:
10.1016/j.bmcl.2013.07.050
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center