4EBV

Structure of Focal Adhesion Kinase catalytic domain in complex with novel allosteric inhibitor

Summary for 4EBV

• Entry DOI: 10.2210/pdb4ebv/pdb
• Descriptor: Focal adhesion kinase 1, 8-(4-ethylphenyl)-5-methyl-2,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide, ISOPROPYL ALCOHOL, ... (4 entities in total)
• Functional Keywords: kinase domain, allosteric inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell junction, focal adhesion: Q05397
• Total number of polymer chains: 1
• Total formula weight: 35553.91

Authors

Skene, R.J.,Hosfield, D.J. (deposition date: 2012-03-25, release date: 2012-08-22, Last modification date: 2024-10-09)

Primary citation

Iwatani, M.,Iwata, H.,Okabe, A.,Skene, R.J.,Tomita, N.,Hayashi, Y.,Aramaki, Y.,Hosfield, D.J.,Hori, A.,Baba, A.,Miki, H.
Discovery and characterization of novel allosteric FAK inhibitors.
Eur.J.Med.Chem., 61:49-60, 2013

PubMed Abstract: 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.

PubMed: 22819505
DOI: 10.1016/j.ejmech.2012.06.035

Experimental method

X-RAY DIFFRACTION (1.67 Å)