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

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

doi:10.1016/j.ccr.2004.06.009

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

Cancer Cell. 2004 Jul;6(1):33-43. doi: 10.1016/j.ccr.2004.06.009.

Authors

Andrew L Kung¹, 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

Affiliation

¹ Dana-Farber Cancer Institute and Harvard Medical School, Massachusetts 02115, USA. andrew_kung@dfci.harvard.edu

PMID: 15261140
DOI: 10.1016/j.ccr.2004.06.009

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology*
Aryl Hydrocarbon Receptor Nuclear Translocator
Carcinoma, Hepatocellular / pathology
Cell Hypoxia / genetics
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Colonic Neoplasms / 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
Nuclear Proteins / metabolism*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Prostatic Neoplasms / therapy
Protein Binding / drug effects
Receptors, Aryl Hydrocarbon / genetics
Receptors, Aryl Hydrocarbon / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Trans-Activators / genetics
Trans-Activators / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic / drug effects*
Transplantation, Heterologous
Vascular Endothelial Growth Factor A / metabolism

Substances

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