Author/Authors :
Kung، نويسنده , , Andrew L and Zabludoff، نويسنده , , Sonya D and France، نويسنده , , Dennis S and Freedman، نويسنده , , Steven J and Tanner، نويسنده , , Elizabeth A and Vieira، نويسنده , , Annelisa and Cornell-Kennon، نويسنده , , Susan and Lee، نويسنده , , Jennifer M. Wang، نويسنده , , Beqing and Wang، نويسنده , , Jamin and Memmert، نويسنده , , Klaus and Naegeli، نويسنده , , Hans-Ulrich and Petersen، نويسنده , , Frank and Eck، نويسنده , , Michael J and Bair، نويسنده , , Kenneth W and Wood، نويسنده , , Alexander W and Livingston، نويسنده , , David M، نويسنده ,
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.
