Abstract
Two novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30).
Keywords:
Diazepine; HSP90 inhibitor; Macrocycle; Oaxazepine; Structure based design.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
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Adenosine Triphosphate / chemistry
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Adenosine Triphosphate / metabolism
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Amides / chemistry*
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Amides / metabolism
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Amides / pharmacology
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Animals
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Azepines / chemistry
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Benzamides / chemistry
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Benzamides / metabolism
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Benzodiazepines / chemistry*
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Benzodiazepines / metabolism
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Benzodiazepines / pharmacology
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Binding Sites
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Cell Membrane Permeability / drug effects
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Crystallography, X-Ray
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Dogs
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Drug Evaluation, Preclinical
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Indoles / chemistry*
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Indoles / metabolism
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Indoles / pharmacology
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Madin Darby Canine Kidney Cells
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Molecular Docking Simulation
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Oxazepines / chemistry*
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Oxazepines / metabolism
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Oxazepines / pharmacology
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Protein Binding
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Protein Structure, Tertiary
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Structure-Activity Relationship
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ortho-Aminobenzoates / chemistry
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ortho-Aminobenzoates / metabolism
Substances
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2-fluoro-6-(tetrahydrofuran-3-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide
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Amides
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Azepines
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Benzamides
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HSP90 Heat-Shock Proteins
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Indoles
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Oxazepines
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ortho-Aminobenzoates
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Benzodiazepines
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Adenosine Triphosphate