Novel Bisphosphonate Conjugates in Myeloma Bone Disease

新型双膦酸盐缀合物治疗骨髓瘤骨病

• 批准号: 6992594
• 负责人: I ROSS GARRETT
• 金额: $ 9.92万
• 依托单位: OSTEOSCREEN, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-27 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6992594
• 关键词: alendronate; antineoplastics; apoptosis; bone disorder; bone marrow; cell line; chemical conjugate; chemoprevention; drug design /synthesis /production; drug screening /evaluation; genetically modified animals; laboratory mouse; multiple myeloma; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; osteogenesis; osteopenia; protease inhibitor; skeletal disorder chemotherapy; xenotransplantation

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.

描述（由申请人提供）：最近发现抑制蛋白酶体的化合物在骨髓瘤的临床前模型以及患者中非常有效。我们已经发现，这些药物引起骨髓瘤细胞凋亡，以及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丢失，蛋白酶体抑制剂具有治疗骨髓瘤及其相关骨疾病的潜力。然而，与蛋白酶体抑制剂全身给药相关的不良反应范围限制了其潜在效用。在本申请中，我们的目标是通过使用二膦酸盐阿仑膦酸盐将蛋白酶体抑制剂PS-341靶向骨以形成新的肽硼酸-二膦酸盐缀合物来规避与全身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，并确定其在完善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，并在一个方案中测试对已确定疾病的功效。如果该化合物是有效的，则将考虑将其开发为治疗候选物。