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Expanding the Scope of Small Molecule Transcription Activators
Author(s) -
Casey Ryan James,
Desaulniers JeanPaul,
Leathen Mathew L,
Hojfeldt Jonas W,
Mapp Anna K
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.651.2
Subject(s) - activator (genetics) , transcription factor , transcription (linguistics) , small molecule , microbiology and biotechnology , chemistry , promoter , biology , gene , gene expression , biochemistry , philosophy , linguistics
Mis‐regulated transcription correlates strongly with many human disease states ranging from cancer to diabetes. Synthetic molecules that can directly perturb gene expression patterns thus hold great therapeutic potential. However, therapeutically useful activators that up‐regulate transcription have yet to be described. To this end, we have developed small molecules based on an isoxazolidine scaffold to serve as transcriptional activation domain (TAD) replacements. Such molecules can up‐regulate transcription in living cells when localized to DNA at an EC 50 of 33 nM and the maximal activity of 80‐fold activation occurs at 1 μM. These molecules can be used to probe activator and co activator function which provides valuable insight into activator recruitment of transcription factors. Specifically, these molecules can inhibit activator co‐activator interactions and provide insight into how activators bind their targets. Through structure‐activity based studies, we identified key residues important for transcription and establish a relationship between hydrophobicity and activation. Further, to confirm the importance of a structured scaffold, we synthesized a peptide with the similar functionality of our most important isoxazolidine and transcription activation was attenuated. These conclusions lead us to believe that activators should be well structured and have a blend of hydrophobicity and polar functionality. The NSF (CAREER), the American Cancer Society (RSG 05‐195‐01) and the Sloan Foundation funded this research.