title: Structure-based discovery of cellular-active allosteric inhibitors of FAK.
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.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. naoki.tomita@takeda.com
authors: Naoki
authors: N
authors: Tomita
authors: Yoko
authors: Y
authors: Hayashi
authors: Shinkichi
authors: S
authors: Suzuki
authors: Yoshimasa
authors: Y
authors: Oomori
authors: Yoshio
authors: Y
authors: Aramaki
authors: Yoshihiro
authors: Y
authors: Matsushita
authors: Misa
authors: M
authors: Iwatani
authors: Hidehisa
authors: H
authors: Iwata
authors: Atsutoshi
authors: A
authors: Okabe
authors: Yoshiko
authors: Y
authors: Awazu
authors: Osamu
authors: O
authors: Isono
authors: Robert J
authors: RJ
authors: Skene
authors: David J
authors: DJ
authors: Hosfield
authors: Hiroshi
authors: H
authors: Miki
authors: Tomohiro
authors: T
authors: Kawamoto
authors: Akira
authors: A
authors: Hori
authors: Atsuo
authors: A
authors: Baba
mesh_terms: D000495:Allosteric Site; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: C583198:8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo(4,3-c)(2,1)benzothiazine 4,4-dioxide; D000970:Antineoplastic Agents; D003499:Cyclic S-Oxides; D006575:Heterocyclic Compounds, 3-Ring; D047428:Protein Kinase Inhibitors; D013843:Thiazines; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases