MEDI 465 |
| Protein•protein interactions regulate diverse and complex biological processes such as transcription and apoptosis. The ability to facilitate or inhibit protein•protein interactions with small molecules has tremendous promise in the development of therapeutics for diseases associated with the misregulation of protein assembly. A class of protein surfaces that remains particularly difficult to recognize is transcriptional co-activator proteins. Co-activator proteins serve as a bridge between DNA-bound transcription factors and components of the RNA polymerase holoenzyme. A variety of small molecule isoxazolidines and short isoxazolidine oligomers containing functionality similar to natural activators have been synthesized and evaluated for co-activator binding and ability to activate transcription. The ligands were found to bind the transcriptional co-activator CREB binding protein through its KIX domain using NMR spectroscopy and to activate transcription 70-80 fold in a cell based transcription assay. These results demonstrate the potential of small molecule based therapies for diseases caused by transcriptional misregulation. |
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General Oral Session
1:30 PM-4:50 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |