Abstract
Novel small molecule inhibitors of heat shock protein 90 (Hsp90) were discovered with the help of a fragment based drug discovery approach (FBDD) and subsequent optimization with a combination of structure guided design, parallel synthesis and application of medicinal chemistry principles. These efforts led to the identification of compound 18 (NMS-E973), which displayed significant efficacy in a human ovarian A2780 xenograft tumor model, with a mechanism of action confirmed in vivo by typical modulation of known Hsp90 client proteins, and with a favorable pharmacokinetic and safety profile.
Keywords:
Anti-cancer agents; Fragment based drug discovery; Tumor cell proliferation inhibition.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Binding Sites
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Biomarkers, Tumor / metabolism
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Catalytic Domain
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Cell Line, Tumor
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Cell Survival / drug effects
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Crystallography, X-Ray
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Drug Design
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Drug Evaluation, Preclinical
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Female
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Isoxazoles / chemistry*
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Isoxazoles / pharmacology*
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Isoxazoles / therapeutic use
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Protein Binding / drug effects
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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HSP90 Heat-Shock Proteins
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Isoxazoles
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NMS-E973