Protein tyrosine phosphatases (PTPs) are a class of enzymes that have just recently been linked to various diseases including cancer, cardiovascular, immunological, infectious, neurological, and metabolic diseases. Targeting these proteins with specific small molecules is a challenge yet to be mastered, in particular because of membrane impermeability of most known compounds that inhibit PTPs in vitro. Thus, new concepts for delivering highly effective PTP inhibitors are clearly needed and could prove as generally applicable methods. The Vaccinia H1-related (VHR) PTP is a dual-specific Erk and Jnk phosphatase, the loss of which causes specific cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells without detrimental effects on normal cells. Preliminary results suggest that VHR is upregulated in several cervix cancer cell lines, in squamous intraepithelial lesions, and squamous cell carcinomas of the uterine cervix. Specific small-molecule inhibitors of VHR could establish this phosphatase as a novel and promising drug target for the treatment of cervical cancer and may be a starting point for developing drugs to treat the disease. With novel and in vitro highly active sulfonic acid lead structures from a chemical library screening effort in hand, we will attempt to overcome the inherent impermeability issues of these extremely effective VHR inhibitors, by developing a new prodrug delivery technology for sulfonic acid PTP/VHR inhibitors. We will synthesize a variety of sulfonic acid esters, which will be more lipophilic than their corresponding free acids and therefore should penetrate cell membranes much more readily. We will evaluate these prodrugs in vitro as well as in cell-based assays for their ability to cross membranes and to be processed by cellular enzymes to regain their biological activity. Finally we will take these compounds and test them in cervix cancer cell lines to prove VHR as a suitable drug target for the treatment of cervical cancer, a disease that effects 13,000 women each year in the US alone. The goal of this proposal is to develop a new technology for effective delivery of drugs targeting a class of enzymes called protein tyrosine phosphatases (PTPs). PTPs have been recently implicated with numerous human diseases, including cancer, cardiovascular, immunological, infectious, neurological, and metabolic diseases. The specific PTP we are focusing on is called VHR. Our preliminary data clearly suggest that VHR is critical for the development of cervical cancer. ? ? ?
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