We have taken a multipronged approach to the identification of novel sumoylation inhibitors. These advances are divided into two areas, based on screening and design-based approaches:1. Development of a high throughput screen to identify sumoylation inhibitors. A major goal of this project is to carry out a high throughput screen to identify novel small molecule sumoylation inhibitors. My laboratory has developed a completely novel biochemical assay to monitor a reconstituted sumoylation cascade using recombinant proteins. In the past year we have optimized and miniaturized the assay, and completed two pilot screens in collaboration with NCI's Molecular Targets Laboratory (MTL). We hope to accomplish a full screen by the end of 2012. Once completed, this screen will provide the lead molecules for further medicinal chemistry and/or total synthesis efforts which will be carried out in the lab. After lead compounds are identified, we will pursue their synthesis and characterize their biochemical mechanism of action. Chemistry efforts will focus on the optimization of physical properties such as potency, cell permeability, and solubility, and will be studied using a variety of techniques such as X-Ray crystallographic (In collaboration with David Waugh) and other biophysical means. My laboratory will study enzyme inhibitor kinteics, while several collaborators (Ji Luo, Michael Keuhn) have already agreed to use identified inhibitors in other, more advanced genetic and mouse model systems to evaluate the anticancer potential of sumoylation inhibitors. 2. Structure based design of novel inhibitors. In collaboration with David Waugh, we are pursuing the structure based design of novel inhibitors of sumoylation enzymes. This is a fragment based drug design approach, whereby we use X-Ray crystallographic analysis of the enzymes to identify fragments capable of interacting with the protein of interest in a defined way. These fragments may then be optimized in to more druglike inhibitors using a medicinal chemistry approach, coupled with biophysical and biochemical analysis. In addition, we are pursuing peptide- and peptidomimetic molecules that bind to sumoylation enzymes in an effort to identify drugable molecular interactions on several enzymes.
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