Pim 1 protein kinase as a target for drug discovery

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The goals of this proposal are to validate the hypothesis that the protein kinase Pim-1 is a potential target for chemotherapy development. Pim-1 protein kinase was cloned as a retroviral insertion point in a screen for genes that enhance tumorigenesis by c-myc. The observation that transgenic mice that carry this protein have an elevated incidence of T- cell lymphomas, and that these mice are extremely sensitive to carcinogen treatment, further suggests that Pim is important in tumorigenesis. Our results demonstrate that the Pim-1 protein kinase is a nuclear enzyme that regulates the levels of bcl-2 mRNA and mdm2 protein, suggesting that Pim-1 may effect the function of p53. The Aims of this proposal are to: (1) determine whether Pim activity is elevated in various tumor types, (2) examine whether Pim regulates specific pathways necessary for tumorigenesis and (3) complete a structural comparison of the Pim to other protein kinases, and (4) suggest potential lead compounds for drug discovery and develop peptidomimetics. The results obtained in this proposal will provide the necessary impetus to target drug discovery towards finding inhibitors of Pim activity. We will define which tumors over-express Pim, the biologic activity of this protein kinase, and develop a structural model for its function. Because other protein kinases have been successfully targeted and drugs are now in the clinic, it is highly likely that inhibitors of this protein kinase could be developed.