Abstract
We recently identified bis(amide) CCG-1423 (1) as a novel inhibitor of RhoA/C-mediated gene transcription that is capable of inhibiting invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. An initial structure-activity relationship study focusing on bioisosteric replacement of the amides and conformational restriction identified two compounds, 4g and 8, with improved selectivity for inhibition of RhoA/C-mediated gene transcription and attenuated cytotoxicity relative to 1. Both compounds were also capable of inhibiting cell invasion with equal efficacy to 1 but with less attendant cytotoxicity.
Copyright 2009 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anilides / chemical synthesis
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Anilides / chemistry*
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Anilides / toxicity
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Aniline Compounds / chemical synthesis*
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Aniline Compounds / chemistry
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Aniline Compounds / toxicity
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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Benzamides / toxicity
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Cell Line, Tumor
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / toxicity
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Humans
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Male
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Neoplasm Invasiveness
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Oncogene Proteins, Fusion / antagonists & inhibitors
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / toxicity
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Prostatic Neoplasms / drug therapy
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Structure-Activity Relationship
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Trans-Activators
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Transcription, Genetic
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rhoA GTP-Binding Protein / antagonists & inhibitors
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism*
Substances
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Anilides
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Aniline Compounds
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Benzamides
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CCG 1423
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DNA-Binding Proteins
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Enzyme Inhibitors
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MRTFA protein, human
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Oncogene Proteins, Fusion
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Piperidines
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Trans-Activators
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rhoA GTP-Binding Protein