Novel Bisphosphonate Conjugates in Myeloma Bone Disease

描述（由申请人提供）：抑制蛋白酶体的化合物最近被发现对骨髓瘤的临床前模型和患者都非常有效。我们发现这些药物引起骨髓瘤细胞凋亡，并刺激成骨细胞分化和骨形成。由于骨髓瘤细胞在肿瘤沉积部位引起严重的骨质流失，蛋白酶体抑制剂具有治疗骨髓瘤及其相关骨病的潜力。然而，与全身施用蛋白酶体抑制剂相关的副作用范围限制了它们的潜在效用。在本应用中，我们的目标是通过使用双膦酸盐阿仑膦酸盐形成一种新型肽硼酸-双膦酸盐偶联物，将蛋白酶体抑制剂PS-341靶向到骨，从而规避与系统性蛋白酶体抑制相关的毒性。我们还将测试该化合物的稳定性和水解速率，并确定其在成熟的骨髓瘤临床前模型中的作用。我们计划在预防方案中检查这种化合物的功效，并在既定疾病的方案中测试功效。如果该化合物是有效的，那么它将被考虑作为治疗候选药物进行开发。

DESCRIPTION (provided by applicant): 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.