Abstract
We have discovered nanomolar inhibitors of TNF-alpha convertase (TACE) comprised of a novel spirocyclic scaffold and either a carboxylate or hydroxamate zinc binding moiety. X-ray crystal structures and computer models of selected compounds binding to TACE explain the observed SAR. We report the first TACE X-ray crystal structure for an inhibitor with a carboxylate zinc ligand.
MeSH terms
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ADAM Proteins / antagonists & inhibitors*
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ADAM17 Protein
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Carboxylic Acids / chemistry*
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Carboxylic Acids / pharmacology
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Computer Simulation
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Crystallography, X-Ray
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Hydroxamic Acids / chemistry*
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Hydroxamic Acids / pharmacology
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Ligands
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Models, Molecular
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Protein Binding
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology
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Structure-Activity Relationship
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Zinc
Substances
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Carboxylic Acids
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Hydroxamic Acids
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Ligands
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Spiro Compounds
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ADAM Proteins
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ADAM17 Protein
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Zinc