Multidimensional Chemical Genetic Analysis of Diversity-Oriented Synthesis-Derived Deacetylase Inhibitors Using Cell-Based Assays

Systematic chemical genetics aims to explore the space representing interactions between small molecules and biological systems. Beyond measuring binding interactions and enzyme inhibition, measuring changes in the activity of proteins in intact signaling networks is necessary. Toward this end, we a...

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Bibliographic Details
Published in:Chemistry & biology 2003-05, Vol.10 (5), p.383-396
Main Authors: Haggarty, Stephen J., Koeller, Kathryn M., Wong, Jason C., Butcher, Rebecca A., Schreiber, Stuart L.
Format: Article
Language:English
Subjects:
Acetylation
Amidohydrolases - antagonists & inhibitors
Anilides - analysis
Cell Line, Tumor
Combinatorial Chemistry Techniques
Enzyme Inhibitors - analysis
Enzyme Inhibitors - chemistry
Genetic Techniques
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids - analysis
Hydroxamic Acids - chemistry
Lysine - chemistry
Molecular Structure
Principal Component Analysis
Structure-Activity Relationship
Tubulin - chemistry
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Summary:Systematic chemical genetics aims to explore the space representing interactions between small molecules and biological systems. Beyond measuring binding interactions and enzyme inhibition, measuring changes in the activity of proteins in intact signaling networks is necessary. Toward this end, we are partitioning chemical space into regions with different biological activities using a panel of cell-based assays and small molecule “chemical genetic modifiers.” Herein, we report on the use of this methodology for the discovery of 617 small molecule inhibitors of histone deacetylases from a multidimensional screen of an encoded, diversity-oriented synthesis library. Following decoding of chemical tags and resynthesis, we demonstrate the selectivity of one inhibitory molecule (tubacin) toward α-tubulin deacetylation and another (histacin) toward histone deacetylation. These small molecules will facilitate dissecting the role of acetylation in a variety of cell biological processes.
ISSN:1074-5521
1879-1301
DOI:10.1016/S1074-5521(03)00095-4