Targeting PRL Phosphatases for Cancer Therapy

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Protein tyrosine phosphatases (PTPs) are important modulators of signal transduction pathways that regulate a wide range of physiological processes such as cell proliferation and differentiation, progression through the cell cycle, cell-cell communication, cell migration, metabolism, gene transcription, ion channel activity, the immune response and apoptosis/survival decisions. Deregulation of PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. The PRL (phosphatase of regenerating liver) phosphatases represent a novel class of PTPs that are important for controlling cellular growth and invasion. In particular, substantial evidence has accumulated that suggests an oncogenic role for PRL3 in the development of a number of tumorigenesis and metastasis processes. Ectopic expression of PRL3 enhances cell growth, causes cell transformation, and promotes tumor metastasis. Importantly, the phosphatase activity of PRL3 is required for the observed oncogenic activity. Consequently, PRL3 is a highly attractive target for cancer therapy. The goals of this application are to develop potent and selective small molecule PRL3 inhibitors and to evaluate their potential to be used as anti-cancer therapeutics. A multidisciplinary research program involving synthetic chemistry, high throughput screening, enzyme kinetics, cell biology, mutagenesis, and structural biology will be employed to: 1) Design and construct novel combinatorial libraries targeted to PRL3, 2) Identify and characterize potent and selective PRL3 inhibitors from the libraries, 3) Assess the cellular efficacy of the selected PRL3 inhibitors, and 4) Determine the molecular basis of PRL3 inhibition. Successful completion of this project will create a solid foundation upon which novel anti-cancer agents targeted to PRL3 can be developed. In addition, potent and selective PRL3 inhibitors acquired from this project will also serve as research tools to delineate the function of PRL3 in normal physiology and in the pathogenesis of certain cancers. Obtaining this knowledge is vital for understanding the PRL3-mediated tumor growth and metastasis, and for the development of novel anti-cancer therapies targeted to PRL3.