Cancer drug discovery using disordered protein targets

Molecular Kinetics, Inc., Indianapolis IN

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Abstract

DESCRIPTION (provided by applicant): A novel technique for cancer drug discovery, "Disordered Protein Phage Display Assay", is proposed. This new technique will inject new avenues to cancer drug discovery methods since disordered proteins are only recently proven to have promising drug-targetable functions. The basic principle is based on the fact that disordered regions of proteins are more sensitive to protease digestion than ordered regions, whether naturally ordered or induced to be ordered. In Phase I, a model system using paclitaxel and bcl-2 will be used to demonstrate feasibility. This system is chosen because paclitaxel is a known anti-cancer drug and binds to the disordered loop of bcl-2. First, the hypothesis that small molecule (paclitaxel) binding to disordered target (bcl-2) inhibits its degradation by protease will be confirmed. Then the disordered region of bcl-2 will be cloned into a phage display vector and the hybrid will be tested by protease in the presence or absence of paclitaxel. Growth of the phage after protease and paclitaxel exposure indicates protection of the disordered region by paclitaxel. The ultimate final product will be a new methodology and expert analysis to accelerate drug lead identification via interaction with disordered regions of cancer-associated proteins.