Document Detail


Characterization, chemical optimization and anti-tumour activity of a tubulin poison identified by a p53-based phenotypic screen.
MedLine Citation:
PMID:  18971638     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A robust p53 cell-based assay that exploits p53's function as a transcription factor was used to screen a small molecule library and identify bioactive small molecules with potential antitumor activity. Unexpectedly, the majority of the highest ranking hit compounds from this screen arrest cells in mitosis and most of them impair polymerization of tubulin in cells and in vitro. One of these novel compounds, JJ78:1, was subjected to structure-activity relationship studies and optimized leading to the identification of JJ78:12. This molecule is significantly more potent than the original hit JJ78:1, as it is active in cells at two-digit nanomolar concentrations and shows clear antitumor activity in a mouse xenograft model as a single agent. The effects of nocodazole, a well established tubulin poison, and JJ78:12 on p53 levels are remarkably similar, supporting that tubulin depolymerization is the main mechanism by which JJ78:12 treatment leads to p53 activation in cells. In summary, these results identify JJ78:12 as a potential cancer therapeutic, demonstrate that screening for activators of p53 in a cell-based assay is an effective way to identify inhibitors of mitosis progression and highlights p53's sensitivity to alterations during mitosis.
Authors:
Oliver D Staples; Jonathan J Hollick; Johanna Campbell; Maureen Higgins; Anna R McCarthy; Virginia Appleyard; Karen E Murray; Lee Baker; Alastair Thompson; Sebastien Ronseaux; Alexandra M Z Slawin; David P Lane; Nicholas J Westwood; Sonia Lain
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  7     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-12-23     Completed Date:  2009-02-10     Revised Date:  2014-03-17    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3417-27     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / chemical synthesis,  chemistry*,  pharmacology*
Cell Line, Tumor
Drug Screening Assays, Antitumor
Humans
Mice
Micronuclei, Chromosome-Defective / drug effects
Mitosis / drug effects
Mitotic Index
Phenotype
Reproducibility of Results
Structure-Activity Relationship
Tubulin / metabolism
Tubulin Modulators / chemical synthesis,  chemistry*,  pharmacology*
Tumor Suppressor Protein p53 / metabolism*
Grant Support
ID/Acronym/Agency:
6613//Cancer Research UK; A6613//Cancer Research UK; //Medical Research Council
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Tubulin; 0/Tubulin Modulators; 0/Tumor Suppressor Protein p53
Comments/Corrections

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