Structure-based discovery of cellular-active allosteric inhibitors of FAK.
Bioorg Med Chem Lett
; 23(6): 1779-85, 2013 Mar 15.
Article
in En
| MEDLINE
| ID: mdl-23414845
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thiazines
/
Cyclic S-Oxides
/
Protein Kinase Inhibitors
/
Focal Adhesion Protein-Tyrosine Kinases
/
Heterocyclic Compounds, 3-Ring
/
Antineoplastic Agents
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2013
Document type:
Article
Affiliation country:
Japón