A Proteomic Strategy for Inhibiting Cancer-Associated Enzymes

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Cancer remains one of the most prevalent and life-threatening diseases for which effective treatments and cures are rare. The molecular properties special to metastativ carcinomas that support their motile and invasive behavior are complex and ill-defined. One generally accepted notion depicts hydrolytic enzymes, such as proteases and lipases, as critical mediators of the aggressive properties of metastatic tumors. To identify novel cancer-associated hydrolases, Cravatt and coworkers have developed a chemical proteomic strategy referred to as activity-based protein profiling (ABPP) the utilizes active site-directed probes to readout changes in hydrolase function directly in whole cell, issue, and fluid proteomes. In previous reseach efforts, multiple enzyme activities were identified, including several serine proteases and lipases, that were differentially expressed in several different tumor types. Many of these enzyme activities are uncharacterized proteins that may represent new targets for the diagnosis and treatment of cancer and other diseases. The goal of this proposal is to discover potent and selective chemical inhibitors of these novel cancer-associated hydrolases and then test the effects of specific inhibitors on cancer cell proliferation/invasion. In this application, we will apply an multidisciplinary approach, utilizing synthetic chemistry, functional proteomic, and cell biology techniques.