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PDBsum entry 4ebw
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Transferase/transferase inhibitor
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PDB id
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4ebw
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References listed in PDB file
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Key reference
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Title
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Discovery and characterization of novel allosteric fak inhibitors.
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Authors
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M.Iwatani,
H.Iwata,
A.Okabe,
R.J.Skene,
N.Tomita,
Y.Hayashi,
Y.Aramaki,
D.J.Hosfield,
A.Hori,
A.Baba,
H.Miki.
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Ref.
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Eur J Med Chem, 2013,
61,
49-60.
[DOI no: ]
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PubMed id
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Abstract
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Focal adhesion kinase (FAK) regulates cell survival and proliferation pathways.
Here we report the discovery of a highly selective series of
1,5-dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of
allosteric inhibition of FAK. These compounds showed slow dissociation from
unphosphorylated FAK and were noncompetitive with ATP after long preincubation.
Co-crystal structural analysis revealed that the compounds target a novel
allosteric site within the C-lobe of the kinase domain, which induces disruption
of ATP pocket formation leading to the inhibition of kinase activity. The
potency of allosteric inhibition was reduced by phosphorylation of FAK. Coupled
SAR analysis revealed that N-substitution of the fused pyrazole is critical to
achieve allosteric binding and high selectivity among kinases.
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