Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway.
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.
Kung
Andrew L
AL
Dana-Farber Cancer Institute and Harvard Medical School, Massachusetts 02115, USA. andrew_kung@dfci.harvard.edu
Zabludoff
Sonya D
SD
France
Dennis S
DS
Freedman
Steven J
SJ
Tanner
Elizabeth A
EA
Vieira
Annelisa
A
Cornell-Kennon
Susan
S
Lee
Jennifer
J
Wang
Beqing
B
Wang
Jamin
J
Memmert
Klaus
K
Naegeli
Hans-Ulrich
HU
Petersen
Frank
F
Eck
Michael J
MJ
Bair
Kenneth W
KW
Wood
Alexander W
AW
Livingston
David M
DM
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
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