Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway.

Abstract	Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and requires coactivation by the CBP and p300 transcriptional coactivators. Through a target-based high-throughput screen, we identified chetomin as a disrupter of HIF binding to p300. At a molecular level, chetomin disrupts the structure of the CH1 domain of p300 and precludes its interaction with HIF, thereby attenuating hypoxia-inducible transcription. Systemic administration of chetomin inhibited hypoxia-inducible transcription within tumors and inhibited tumor growth. These results demonstrate a therapeutic window for pharmacological attenuation of HIF activity and further establish the feasibility of disrupting a signal transduction pathway by targeting the function of a transcriptional coactivator with a small molecule.
Authors	Andrew L Kung, Sonya D Zabludoff, Dennis S France, Steven J Freedman, Elizabeth A Tanner, Annelisa Vieira, Susan Cornell-Kennon, Jennifer Lee, Beqing Wang, Jamin Wang, Klaus Memmert, Hans-Ulrich Naegeli, Frank Petersen, Michael J Eck, Kenneth W Bair, Alexander W Wood, David M Livingston
Journal	Cancer cell (Cancer Cell) Vol. 6 Issue 1 Pg. 33-43 (Jul 2004) ISSN: 1535-6108 [Print] United States
PMID	15261140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	ARNT protein, human Anti-Bacterial Agents Arnt protein, mouse DNA-Binding Proteins Disulfides HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Indole Alkaloids Nuclear Proteins Receptors, Aryl Hydrocarbon Trans-Activators Transcription Factors Vascular Endothelial Growth Factor A Erythropoietin Aryl Hydrocarbon Receptor Nuclear Translocator chetomin Luciferases E1A-Associated p300 Protein Ep300 protein, mouse
Topics	Animals Anti-Bacterial Agents (pharmacology) Aryl Hydrocarbon Receptor Nuclear Translocator Carcinoma, Hepatocellular (pathology) Cell Hypoxia (genetics) Colonic Neoplasms (metabolism, pathology, therapy) DNA-Binding Proteins Disulfides E1A-Associated p300 Protein Erythropoietin (metabolism) Humans Hypoxia-Inducible Factor 1, alpha Subunit Indole Alkaloids Liver Neoplasms (pathology) Luciferases (metabolism) Male Mice Mice, Nude Nuclear Proteins (genetics, metabolism) Prostatic Neoplasms (metabolism, pathology, therapy) Protein Binding (drug effects) Receptors, Aryl Hydrocarbon (genetics, metabolism) Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Trans-Activators (genetics, metabolism) Transcription Factors (genetics, metabolism) Transcription, Genetic (drug effects) Transplantation, Heterologous Vascular Endothelial Growth Factor A (metabolism)

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