PDB 4I4F deposited: 2012-11-27 modified: 2013-04-24
Title Structure of Focal Adhesion Kinase catalytic domain in complex with an allosteric binding pyrazolobenzothiazine compound.
Authors Aramaki, Y., Awazu, Y., Baba, A., Hayashi, Y., Hori, A., Hosfield, D.J., Isono, O., Iwata, H., Iwatani, M., Kawamoto, T., Matsushita, Y., Miki, H., Okabe, A., Oomori, Y., Skene, R.J., Suzuki, S., Tomita, N.
Structure factors resolution 1.75 rfactor 0.18612 rfree 0.22846
DPI 0.35 theoretical min: 0.13
Related PDB Entries 4I4E

In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50=0.64μM) and in cellular assays (IC50=7.1μM). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents.

Bioorg.Med.Chem.Lett. 2013 Mar; 23(6):1779-1785 doi:10.1016/j.bmcl.2013.01.047

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL2331389
PubMed 23414845 BMCLE8
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4I4F/0 4I4F 0 monomer 0 1 2 2108