PDB 4EBW deposited: 2012-03-25 modified: 2013-03-27
Title Structure of Focal Adhesion Kinase catalytic domain in complex with novel allosteric inhibitor
Authors Aramaki, Y., Baba, A., Hayashi, Y., Hori, A., Hosfield, D.J., Iwata, H., Iwatani, M., Miki, H., Okabe, A., Skene, R.J., Tomita, N.
Structure factors resolution 2.65 rfactor 0.18209 rfree 0.27349
DPI 1.14 theoretical min: 0.44
Related PDB Entries 4EBV

Focal adhesion kinase (FAK) regulates cell survival and proliferation pathways. Here we report the discovery of a highly selective series of 1,5-dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of allosteric inhibition of FAK. These compounds showed slow dissociation from unphosphorylated FAK and were noncompetitive with ATP after long preincubation. Co-crystal structural analysis revealed that the compounds target a novel allosteric site within the C-lobe of the kinase domain, which induces disruption of ATP pocket formation leading to the inhibition of kinase activity. The potency of allosteric inhibition was reduced by phosphorylation of FAK. Coupled SAR analysis revealed that N-substitution of the fused pyrazole is critical to achieve allosteric binding and high selectivity among kinases.

Eur.J.Med.Chem. 2013 Mar; 61:49-60 doi:10.1016/j.ejmech.2012.06.035

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL2346629
PubMed 22819505 EJMCA5
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4EBW/0 4EBW 0 monomer 0 1 1 1961