Small Molecule Inhibitors of K13-Induced NF-kB Activation

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DESCRIPTION (provided by applicant): PROJECT SUMMARY Kaposi's sarcoma associated herpes virus (KSHV), also known as Human herpes virus 8 (HHV8), is the most frequent cause of malignancy among AIDS patients. Infection with KSHV has been linked to the occurrence of Kaposi's sarcoma (KS) and several lymphoproliferative disorders including primary effusion lymphoma (PEL), multicentric Castleman's disease and immunoblastic/plasmablastic lymphomas. Because of underlying immunosuppression, KSHV-associated cancers have extremely poor prognosis when treated with conventional chemotherapy and there is urgent need for more effective and less toxic therapies for these disorders. However, the exact mechanism of action of KSHV in the pathogenesis of these disorders is still unclear. We have discovered that K13, a KSHV-encoded vFLIP (viral FLICE inhibitory protein), possesses the unique abilities to activate the classical and alternative NF-?B pathways by interacting with different components of the I?B kinase (IKK) complex. We have further demonstrated that K13 is an oncogene that mediates increased cellular proliferation, transformation, cytokine secretion and protection against growth factor withdrawal-induced apoptosis via NF?B activation. Thus, we believe that K13 is a pivotal player in the pathogenesis of KSHV-associated lymphoproliferative disorders and an ideal candidate for development of molecularly targeted therapies. The primary goal of this proposal is to develop a high throughput assay to isolate small molecule inhibitors of K13-induced NF?B activation and test their ability to block its biological activities using assays established in our laboratory. We hope that these studies will not only lead to a better understanding of the various biological functions of K13 but also to the identification of less toxic and more effective molecularly targeted agents for the treatment of KSHV-associated cancers. PROJECT NARRATIVE Infection with the Kaposi's sarcoma associated herpesvirus (KSHV) has been linked to a number of human cancers. The goal of this project is to develop a screening assay to identify inhibitors of K13, a key protein encoded by this virus. Such inhibitors will lead to a better understanding of the K13 protein in the pathogenesis of KSHV-associated cancers and to the development of more effective drugs for their treatment.