||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.
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