losartan-potassium and chetomin

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.

Topics: Animals; Anti-Bacterial Agents; Aryl Hydrocarbon Receptor Nuclear Translocator; Carcinoma, Hepatocellular; Cell Hypoxia; Colonic Neoplasms; Disulfides; DNA-Binding Proteins; E1A-Associated p300 Protein; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Indole Alkaloids; Liver Neoplasms; Luciferases; Male; Mice; Mice, Nude; Nuclear Proteins; Prostatic Neoplasms; Protein Binding; Receptors, Aryl Hydrocarbon; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Trans-Activators; Transcription Factors; Transcription, Genetic; Transplantation, Heterologous; Vascular Endothelial Growth Factor A