Abstract
With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.
Copyright © 2012 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 / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Azabicyclo Compounds / chemistry*
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Azabicyclo Compounds / pharmacokinetics
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Azabicyclo Compounds / pharmacology
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Azabicyclo Compounds / therapeutic use*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Discovery
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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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Mice
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Models, Molecular
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Neoplasms / pathology
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Phthalic Acids / chemistry*
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Phthalic Acids / pharmacokinetics
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Phthalic Acids / pharmacology
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Phthalic Acids / therapeutic use*
Substances
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Antineoplastic Agents
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Azabicyclo Compounds
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HSP90 Heat-Shock Proteins
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Phthalic Acids
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XL 888