Angiogenesis, the programmed growth blood vessels, is tightly controlled by a number of specific mitogenic factors, among which vascular endothelial growth factor (VEGF) and its receptors play a central role. The levels of VEGF are up-regulated across a broad range of tumors and are involved in key aspects of cancer biology. A hallmark of many cancers, chronic hypoxia, in conjunction with activation of certain oncogenic signaling pathways, is responsible for the elevated levels of VEGF and is associated with invasion and altered energy metabolism. Because tight control of hypoxia-inducible gene expression is critical for cellular existence, the goal of primary importance has been to develop methods of controlling hypoxia-inducible genes in malignant cells while leaving normal cells unaffected. To address this goal, we seek to uncover synthetic molecules that specifically regulate hypoxia-inducible transcription. We hypothesize that the process of transcription could be effectively modulated via disruption of key transcription factor-coactivator interactions involving CH1 domain of protein p300 or the homologous CBP and the C-terminal transactivation domain (C-TAD) of the hypoxia-inducible factor 1(. This complex features short (-helical domains at the interface and suggests that synthetic mimics of these helices would modulate the protein-protein interaction. In this application, we utilize a new class of artificial (-helices with secondary structure that mimics the biologically relevant fragment of HIF-1( C-TAD. In preliminary studies, we have shown that disruption of the Hif-1(/p300 interaction with our synthetic helices results in rapid downregulation of important in cancer progression hypoxia-inducible genes, including VEGF, in cell culture.
Our specific aims are to: (1) to design and synthesize artificial helices as inhibitors of the transcription factor-coactivator complex;(2) evaluate binding thermodynamics of each inhibitor toward their protein targets, test their ability to inhibit the cognate protein-protein interaction in vitro, and (3) test the ability artificial helices to disrupt transcription of HIF-inducible genes in cancer and explore the mechanistic details of this disruption at the molecular level. Combined these three aims will validate our hypothesis and create a foundation for the development of a new class of structure and mechanism-based cancer therapeutics.
The sequencing of the human genome and recent advances in proteomics have led to a better understanding of the relationship between genetic content and disease. As a result, the development of novel therapies based on controlling gene expression in diseased cells has become an increasingly important goal. By combining the art of chemical synthesis with the methods of molecular biology and genetics, we aim to uncover uniquely specific small molecules that act as suppressors of hypoxia-inducible transcription in cancer with the long-term goal of developing new therapeutics for treatment of aerobic glycolysis and angiogenesis.
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