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

作者: Andrew L Kung , Sonya D Zabludoff , Dennis S France , Steven J Freedman , Elizabeth A Tanner

DOI: 10.1016/J.CCR.2004.06.009

关键词: Signal transductionSystemic administrationBiologyCell biologyTranscription (biology)BlockadeHomeostasisMolecular biologyHypoxia-Inducible Factor PathwayCoactivationSmall molecule

摘要: Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and requires coactivation CBP p300 coactivators. Through target-based high-throughput screen, we identified chetomin as disrupter of HIF binding to p300. At molecular level, disrupts structure CH1 domain precludes its interaction with HIF, thereby attenuating transcription. Systemic administration inhibited transcription within tumors tumor growth. These results demonstrate therapeutic window for pharmacological attenuation activity further establish feasibility disrupting signal transduction targeting function coactivator small molecule.

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