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Transcriptional tools: Small molecules for modulating CBP KIX‐dependent transcriptional activators
Author(s) -
Bates Caleb A.,
Pomerantz William C.,
Mapp Anna K.
Publication year - 2011
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.21548
Subject(s) - chemistry , creb , transcription (linguistics) , creb binding protein , small molecule , transcription factor , transcriptional regulation , microbiology and biotechnology , biophysics , plasma protein binding , binding site , transcriptional activity , computational biology , biochemistry , biology , gene , linguistics , philosophy
Abstract Previously it was demonstrated that amphipathic isoxazolidines are able to functionally replace the transcriptional activation domains of endogenous transcriptional activators. In addition, in vitro binding studies suggested that a key binding partner of these molecules is the CREB Binding Protein (CBP), more specifically the KIX domain within this protein. Here we show that CBP plays an essential role in the ability of isoxazolidine transcriptional activation domains to activate transcription in cells. Consistent with this model, isoxazolidines are able to function as competitive inhibitors of the activators MLL and Jun, both of which utilize a binding interaction with KIX to up‐regulate transcription. Further, modification of the N2 side chain produced three analogs with enhanced potency against Jun‐mediated transcription, although increased cytotoxicity was also observed. Collectively these small KIX‐binding molecules will be useful tools for dissecting the role of the KIX domain in a variety of pathological processes. © 2010 Wiley Periodicals, Inc. Biopolymers 95: 17–23, 2011.