4I4F

Structure of Focal Adhesion Kinase catalytic domain in complex with an allosteric binding pyrazolobenzothiazine compound.

Summary for 4I4F

• Entry DOI: 10.2210/pdb4i4f/pdb
• Related: 4EBV 4EBW 4I4E
• Descriptor: Focal adhesion kinase 1, ISOPROPYL ALCOHOL, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide, ... (4 entities in total)
• Functional Keywords: phosphorylated on tyrosines, localized to focal adhesions, 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: 32590.77

Authors

Skene, R.J.,Hosfield, D.J. (deposition date: 2012-11-27, release date: 2013-02-06, Last modification date: 2024-11-06)

Primary citation

Tomita, N.,Hayashi, Y.,Suzuki, S.,Oomori, Y.,Aramaki, Y.,Matsushita, Y.,Iwatani, M.,Iwata, H.,Okabe, A.,Awazu, Y.,Isono, O.,Skene, R.J.,Hosfield, D.J.,Miki, H.,Kawamoto, T.,Hori, A.,Baba, A.
Structure-based discovery of cellular-active allosteric inhibitors of FAK.
Bioorg.Med.Chem.Lett., 23:1779-1785, 2013

PubMed Abstract: 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.

PubMed: 23414845
DOI: 10.1016/j.bmcl.2013.01.047

Experimental method

X-RAY DIFFRACTION (1.75 Å)