Prostate cancer remains the most common male malignancy and the second most common cause of cancer-related mortality in most Western societies. The incidence of prostate cancer and corresponding mortality rates vary strikingly among ethnic, racial, and national groups with noteworthy high rates among African Americans. The identification of an up-regulated and strongly expressed anti-genic cancer cells, namely prostate specific membrane antigen (PSMA), has attracted a great deal of attention as a target of immunotherapy. More recently, it has been reported that PSMA possesses at least two specific enzymatic activities have been clearly identified, questions of medical interest remain to be answered for PSMA. Two such questions are: """"""""What is the role of PSMA on the surface of prostate cancer cells?"""""""" and """"""""How would inhibiting PSMA affect the growth, proliferation, or regulation of prostate cancer cells?"""""""" Although the proposed research will not immediately address these questions, it is anticipated that the results of this work will provide the investigators with suitable tools to study these issues in future studies. Furthermore, it is likely that the enzymatic activity of PSMA could be exploited for chemotherapeutic strategies, one of which being the inhibition of its activity by small molecule inhibitors. The objectives of this pilot project proposal are three-fold and are aimed at 1) synthesizing 20 representative inhibitors of PSMA, 2) validating a recently establish HPLC-based assay for PSMA activity, and 3) evaluating the inhibitory potency of these 20 representative analogs against PSMA, and 3) evaluating the inhibitory potency of these 20 representative analogs against PSMA. The successful completion of these objectives of this proposal will position the participating laboratories (both at SFSU and the UCSFCC) for launching a long term collaborative program aimed at developing and evaluating a large library of diverse PSMA inhibitor analogs using a parallel synthesis format and a high-throughput screening method. Relationship to the Overall Priorities and Objectives of the Partnership between SFSU and UCSFCC The research focused of the proposed pilot project is aimed at the development of a primary small library of bioactive agents targeted prostate cancer cells. Therefore, this project will address an important area of health disparity because the incidence of prostate cancer and corresponding mortality rates among African American men who are significantly higher than among other ethnic, racial, and national groups, Furthermore, it is anticipated that this initial partnership between co- leaders of this pilot research project will serve as the foundation for a long-term scientific collaboration between SFSU and the UCSFCC. Because one of the target areas of the U56 MI/CCP is cancer research, the proposed activities outlined in this pilot project fit in well to the objectives of the U56 mission. In addition, the proposed research will provide unique opportunities for both undergraduate and graduate students at the MSI. It is anticipated that the results gathered upon completing the specific objectives of this pilot project will position the collaborating investigators from the MSI (SFSU) and the UCSF Cancer Center for subsequent joint submissions for external grants aimed at developing and evaluating large diverse libraries of putative drug candidates for prostate cancer . A non-science aim for this joint proposal is to increase the number of undergraduate and MS researchers from SFSU applying to the newly established graduate program in Chemistry and Chemical Biology (CCB) at UCSF in which the UCSF collaborators (Criak and Guy) are integrally involved.
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