In the past decade, modulating NF-κB activation through inhibition of the proteasome has emerged as a therapeutic target for the treatment of malignancies and autoimmune diseases. In 2003, the proteasome inhibitor bortezomib was approved by the FDA for the treatment of the plasma cell neoplasm, multiple myeloma. Although bortezomib effectively treats multiple myeloma and has shown promising results for the treatment of these other diseases, its therapeutic potential is limited by peripheral neuropathy, reduced activity in solid tumors, and route of administration restrictions. In 2004, the Tepe laboratory first identified the imidazoline scaffold, as an inhibitor of the NF-κB pathway and subsequently identified the proteasome as its target. The studies presented in this thesis show that the noncompetitive imidazoline proteasome inhibitor, TCH-013, is bioavailable and not hepatotoxic. This compound was also shown to have anti-inflammatory properties and to reduce the broncheoalveolar lavage fluid cellularity in an experimental model of asthma. In addition, we enhanced the efficacy of this molecule by manipulating the functional groups. The result of these studies is the discovery of compound 43, a noncompetitive proteasome inhibitor that is able to overcome bortezomib resistance, is bioavailable, and is effective in an animal model of systemic inflammation. The data presented herein suggest that a modified imidazoline scaffold is an effective, noncompetitive and nontoxic proteasome inhibitor that has therapeutic potential for the treatment of multiple myeloma and asthma.
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