Compounds that inhibit the proteasome have recently been found to be very effective in preclinical models of myeloma as well as in patients. We have found that these agents cause myeloma cell apoptosis, as well as stimulate osteoblast differentiation and bone formation. Since myeloma cells cause profound bone loss at the sites of tumor deposits, proteasome inhibitors have the potential for treating both myeloma as well as its associated bone disease. However, the range of adverse effects associated with systemic administration of proteasome inhibitors is a limitation to their potential utility. In this application, our goal is to circumvent the toxicity associated with systemic proteasome inhibition by targeting the proteasome inhibitor PS-341 to the bone by the use of the bisphosphonate alendronate to form a novel peptide boronic-acid-bisphosphonate conjugate. We will also test the stability and rate of hydrolysis of this compound and determine its effects in a well-established preclinical model of myeloma. We plan to examine the efficacy of this compound in a preventative protocol and in a protocol to test efficacy in established disease. If the compound is efficacious, it will then be considered for development as a therapeutic candidate
