Identification of compounds that modify transcriptional responses to hypoxia

Abstract

The invention provides methods for identifying compounds that can be used to modify transcriptional responses to hypoxia, and use of such compounds in therapeutic and diagnostic methods.

1 . A method of identifying a compound that modulates a transcriptional response to hypoxia in a cell, said method comprising: 
 providing a first transcription factor that is involved in a transcriptional response to hypoxia in a cell, or a fragment thereof;    contacting said first transcription factor, or fragment thereof, with a candidate compound; and    determining whether the candidate compound affects the interaction of the first transcription factor with a second transcription factor, or a fragment thereof.    
     
     
         2 . A method of identifying a compound that modulates a transcriptional response to hypoxia in a cell, said method comprising: 
 providing a first and a second transcription factor that are involved in a transcriptional response to hypoxia in a cell, or fragments thereof;    contacting the first and second transcription factors, or fragments thereof, with a candidate compound; and    determining whether the candidate compound affects the interaction of the first and second transcription factors.    
     
     
         3 . The method of  claim 1 , wherein said first transcription factor comprises a peptide of HIF-1α and said second transcription factor comprises a peptide of p300/CBP.  
     
     
         4 . The method of  claim 3 , wherein said peptide of HIF-1α comprises the TAD-C region of HIF-1α.  
     
     
         5 . The method of  claim 4 , wherein said peptide of HIF-1α consists essentially of the TAD-C region of HIF-1α.  
     
     
         6 . The method of  claim 3 , wherein said peptide of p300/CBP comprises the CH1 region of p300/CBP.  
     
     
         7 . The method of  claim 6 , wherein said peptide of p300/CBP comprises amino acids 302-418, amino acids 302-443, or amino acids 302-528 of p300/CBP.  
     
     
         8 . The method of  claim 6 , wherein said peptide of p300/CBP consists essentially of the CH1 region of p300/CBP.  
     
     
         9 . A method of treating a condition characterized by hypoxia in a patient, hypoxia in a localized tissue, or activation of the HIF-1 pathway, said method comprising administering to the patient a compound that modifies a transcriptional response to hypoxia in the patient.  
     
     
         10 . The method of  claim 9 , wherein the compound decreases a transcriptional response to hypoxia in the patient.  
     
     
         11 . The method of  claim 10 , wherein the condition is cancer or an inflammatory condition of abnormal neovascularization that is mediated by the hypoxia response pathway.  
     
     
         12 . The method of  claim 9 , wherein the compound increases a transcriptional response to hypoxia in the patient.  
     
     
         13 . The method of  claim 12 , wherein the condition is myocardial ischemia, stroke, or an erythropoietin deficiency.  
     
     
         14 . The method of  claim 9 , wherein the compound binds to HIF-1α.  
     
     
         15 . A method of detecting a hypoxic tissue, cell, or tumor in a patient, said method comprising administering to the patient a detectably labeled compound that modifies a transcriptional response to hypoxia in the patient.  
     
     
         16 . The method of  claim 15 , wherein the compound binds to HIF-1α.