title: 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.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, Massachusetts 02115, USA. andrew_kung@dfci.harvard.edu
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Sonya D
authors.initials: SD
authors.lastname: Zabludoff
authors.forename: Dennis S
authors.initials: DS
authors.lastname: France
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Freedman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Tanner
authors.forename: Annelisa
authors.initials: A
authors.lastname: Vieira
authors.forename: Susan
authors.initials: S
authors.lastname: Cornell-Kennon
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.forename: Beqing
authors.initials: B
authors.lastname: Wang
authors.forename: Jamin
authors.initials: J
authors.lastname: Wang
authors.forename: Klaus
authors.initials: K
authors.lastname: Memmert
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Naegeli
authors.forename: Frank
authors.initials: F
authors.lastname: Petersen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wood
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004268:DNA-Binding Proteins; D004220:Disulfides; D050881:E1A-Associated p300 Protein; D004921:Erythropoietin / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026121:Indole Alkaloids; D008113:Liver Neoplasms / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D011485:Protein Binding / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497396:ARNT protein, human; D000900:Anti-Bacterial Agents; C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D004220:Disulfides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026121:Indole Alkaloids; D009687:Nuclear Proteins; D018336:Receptors, Aryl Hydrocarbon; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C001598:chetomin; D008156:Luciferases; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse