Abstract
Chemically diverse fragment hits of focal adhesion kinase (FAK) were discovered by surface plasmon resonance (SPR) screening of our in-house fragment library. Site specific binding of the primary hits was confirmed in a competition setup using a high-affinity ATP-site inhibitor of FAK. Protein crystallography revealed the binding mode of 41 out of 48 selected fragment hits within the ATP-site. Structural comparison of the fragment binding modes with a DFG-out inhibitor of FAK initiated first synthetic follow-up optimization leading to improved binding affinity.
Keywords:
DFG-out; Focal adhesion kinase; Fragment screening; Surface plasmon resonance; X-ray structure.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Crystallography, X-Ray
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Drug Discovery*
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Drug Evaluation, Preclinical
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
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Indoles / chemistry*
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Indoles / pharmacology*
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Structure
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Peptide Fragments / genetics
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Peptide Fragments / pharmacology*
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Small Molecule Libraries* / chemistry
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Small Molecule Libraries* / pharmacology
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Solubility
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology*
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Surface Plasmon Resonance
Substances
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Enzyme Inhibitors
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Indoles
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N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide
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Peptide Fragments
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Small Molecule Libraries
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Sulfonamides
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Focal Adhesion Protein-Tyrosine Kinases