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The University of Southampton

Research project: Tavassoli: Cancer Research

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Our lab carries out research at the interface of organic chemistry and biochemistry; using the tools of molecular biology and synthesis to examine issues of pertinent medical significance. To this end, we search for and study small molecules that modulate cellular processes through targeting protein-protein interactions.

There are several thousand unique protein-protein interactions that control most cellular processes and their inhibition is a viable approach to disease control. However, the search for such inhibitors by conventional methods presents a sizable challenge and is therefore little explored in the search for new pharmaceuticals.

By using the recently developed tools of chemical biology, we have developed methodology that allows the rapid screening of a biosynthesized library of 10^8 cyclic peptides against any chosen protein-protein interaction. We have used this method to uncover inhibitors of several biologically important processes (for an example see Angewandte Chemie, 2005, 44, 2760).

Our current efforts are directed towards the inhibition of the dimerization of the two subunits of hypoxia inducible factor-1 (HIF-1) and HIF-2, (a process that has been shown to control blood vessel formation in tumors), and the inhibition of the homo and heterodimerization of the c-terminal binding proteins.

Inhibition of HIF-1 Dimerization
Growth of primary and metastatic tumors is dependant on angiogenesis, the development of new blood vessels from an existing vascular network, delivering oxygen and nutrients necessary for growth. Hypoxia is a major driver of tumor progression. Hypoxic areas form when the growth of a tumor outstrips local neovascularization, thereby creating areas of inadequate perfusion.

Hypoxia-inducible factor-1 (HIF-1) is the most potent inducer of the expression of genes coding for glycolytic enzymes, vascular endothelial growth factor and erythropoietin. HIF-1 is a heterodimer that consists of HIF-1α, whose expression is tightly regulated by oxygen concentration and HIF-1β, which is a constitutively expressed aryl hydrocarbon receptor nuclear translocator. In the absence of oxygen HIF-1α forms an active complex with HIF-1β and binds to hypoxia-response element, thereby activating the expression of numerous hypoxia response genes.

Analysis of human tumor biopsies revealed dramatic over-expression of HIF-1α was seen in common cancers, furthermore the loss or gain of HIF-1 activity negatively or positively correlated with tumor growth and angiogenesis.

We are currently using or genetic selection system to find inhibitors of HIF-1 dimerization with a view to developing a small molecule inhibitor of angiogenesis in tumors.

Related research groups

Chemical Biology, Diagnostics and Therapeutics
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