Design and Synthesis of Selective Inhibitors for Low Molecular Weight Protein Tyrosine Phosphatase Isoform B
Phosphatases are enzymes that are involved in the cell signal transduction process. When information is not properly conveyed in the cell, problems in the generation of signals necessary for different cellular events such as growth, migration, metabolism, gene transcription, cell-cell communication, ion channel activity, immune response, and apoptosis/survival decisions occur. When these events are not controlled, cancer and other disease states such as diabetes occur. Recent studies have assessed the role of LMW PTPs in cell transformation (conversion to cancerous cells). In theses studies, it was shown that the expression of LWM PTP mRNA and protein is significantly increased in human breast, colon, bladder and kidney tumor samples. Moreover, its enhanced expression was generally prognostic of a more aggressive cancer. It has been suggested that LMW PTP may contribute to cancer invasivity (attacking adjacent tissues) by stabilizing cell-cell contacts. Furthermore, this activity is isozyme specific. Recent data would suggest the two active isoforms (A and B) play opposite roles in the tumorigenic process, with isoform A being anti-oncogenic and isoform B being oncogenic. Inhibitors of LMW PTP isoform B hence may possess potential anti-cancer properties.
The intent of this project will be to virtually screen de novo compound libraries, create and screen combinatorial libraries and design compounds resembling pyridoxal 5’-phosphate (PLP). PLP is a known inhibitor of low molecular weight protein tyrosine phosphatase (LMW PTP). Inhibitors of LMW PTP may possess potential anti-cancer properties by inhibiting dephosphorylation (removal a phosphate group from a protein) of certain receptors. Virtual hits will be tested in vitro.
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