Abstract
The molecular chaperone heat shock protein 90 (HSP90) is a promising target for cancer therapy, as it assists in the stabilization of cancer-related proteins, promoting cancer cell growth, and survival. A novel series of HSP90 inhibitors were discovered by structure-activity relationship (SAR)-based optimization of an initial hit compound 11a having a 4-(4-(quinolin-3-yl)-1 H-indol-1-yl)benzamide structure. The pyrazolo[3,4- b]pyridine derivative, 16e (TAS-116), is a selective inhibitor of HSP90α and HSP90β among the HSP90 family proteins and exhibits oral availability in mice. The X-ray cocrystal structure of the 16e analogue 16d demonstrated a unique binding mode at the N-terminal ATP binding site. Oral administration of 16e demonstrated potent antitumor effects in an NCI-H1975 xenograft mouse model without significant body weight loss.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / therapeutic use
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Benzamides / chemistry*
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Benzamides / metabolism
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Benzamides / therapeutic use
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Binding Sites
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Design*
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Drug Screening Assays, Antitumor
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Mice
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Mice, Nude
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Molecular Conformation
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Molecular Dynamics Simulation
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Neoplasms / drug therapy
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Neoplasms / pathology
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Pyrazoles / chemistry*
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Pyrazoles / metabolism
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Pyrazoles / therapeutic use
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Quinolines / chemistry
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / isolation & purification
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Solubility
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Benzamides
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HSP90 Heat-Shock Proteins
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Pyrazoles
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Quinolines
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Recombinant Proteins
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TAS-116
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quinoline