title: Expanding the repertoire of small molecule transcriptional activation domains.
abstract: Molecules that can reconstitute the function of transcriptional activators hold enormous potential as therapeutic agents and as mechanistic probes. Previously we described an isoxazolidine bearing functional groups similar to natural transcriptional activators that up-regulates transcription 80-fold at 1 microM in cell culture. In this study, we analyze analogs of this molecule to define key characteristics of small molecules that function as transcriptional activation domains in cells. Conformational rigidity is an important contributor to function as is an overall amphipathic substitution pattern. Using these criteria, we identified additional molecular scaffolds with excellent (approximately 60-fold) activity as transcriptional activation domains. These results point the way for the creation of new generations of small molecules with this function.
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Casey
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Desaulniers
authors.forename: Jonas W
authors.initials: JW
authors.lastname: Hojfeldt
authors.forename: Anna K
authors.initials: AK
authors.lastname: Mapp
mesh_terms: D044182:Benzylisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012500:Santonin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015534:Trans-Activators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D044182:Benzylisoquinolines; D007555:Isoxazoles; D015534:Trans-Activators; D012500:Santonin; C013024:hydrastine