Novel targeted therapeutics for multiple myeloma

描述（由申请人提供）：多发性骨髓瘤（MM）是一种无法治愈的肿瘤，其特征是破坏性和进行性骨破坏。 尽管最近在MM的一线治疗方面取得了进展，但几乎所有患者最终都会复发，产生化疗耐药性，并死于该病。硼替佐米的临床研究已经验证了蛋白酶体作为治疗MM和非霍奇金淋巴瘤的治疗靶点。然而，显著的毒性限制了硼替佐米给药的强度，并且其临床疗效受到耐药性出现的阻碍。非常需要将新型有效细胞毒性剂特异性地靶向递送至骨髓瘤细胞所在的骨的方法。该提案的长期目标是开发新的和创新的策略，旨在选择性地将治疗剂递送到骨微环境以有效管理MM。偶联物表明酰胺键的稳定性不允许药物的有效释放，并且高度带电的双膦酸酯部分的存在阻止了细胞对药物的摄取。缀合物，导致细胞毒性降低。在本申请中，我们的目标是合成和评估一系列新的肿瘤激活的骨靶向蛋白酶体抑制剂的功效，其使用双重靶向策略，靶向骨髓瘤细胞在骨微环境中产生的基质金属蛋白酶（MMPs）以切割独特的双膦酸盐-七肽接头。这将使我们能够研究利用MMP-9激活合理设计的前药靶向MM细胞作为一种新的肿瘤特异性治疗的潜力。我们的假设是，通过将二膦酸盐与蛋白酶体抑制剂通过MMP-可切割的七肽连接，1）我们可以将这些化合物靶向骨髓瘤细胞在骨微环境中的沉积物，2）由肿瘤细胞产生的MMP将有效地切割二膦酸盐以释放“弹头”并在局部获得更有效浓度的蛋白酶体抑制剂，和3）肿瘤活化的前药将选择性地杀死肿瘤细胞并防止或减少药物的剂量限制性全身毒性。本发明的具体目的是i）设计和合成新型MMP-9可切割的BP-七肽-PI缀合物，作为在骨微环境中选择性递送PS-341至MM细胞的手段，和ii）在体外和体内研究所提出的化合物。总之，这些筛选将为骨靶向肿瘤活化前药作为治疗MM和其他骨转移癌的有效治疗方式提供验证。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Despite recent advances in the first-line treatment of MM, almost all patients eventually relapse, become chemoresistant, and die of the disease. Clinical studies with Bortezomib have validated the proteasome as a therapeutic target for the treatment of MM and non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of Bortezomib dosing and its clinical efficacy has been hampered by the emergence of resistance. There is great need for methods to target the delivery of novel, effective cytotoxic agents specifically to bone, where myeloma cells reside. The long-term goal of this proposal is to develop novel and innovative strategies aimed at selectively delivering therapeutic agents to the bone microenvironment for effective management of MM. Our recent studies of the bisphosphonate-proteasome inhibitor (BP-PI) conjugates indicate that the stability of the amide linkage does not permit efficient release of the drug and that the presence of the highly charged bisphosphonate moiety prevents cellular uptake of the conjugates, resulting in diminished cytotoxicity. In this application, our goal is to synthesize and evaluate the efficacy of a new series of tumor-activated bone-targeted proteasome inhibitors using a dual targeting strategy that targets matrix metalloproteinases (MMPs) produced by myeloma cells in the bone microenvironment to cleave a unique bisphosphonate-heptapeptide linker. It will enable us to investigate the potential of exploiting MMP-9 to activate prodrugs rationally designed to target MM cells as a new tumor-specific therapy. Our hypothesis is that by linking bisphosphonates to proteasome inhibitors through an MMP-cleavable heptapeptide, 1) we can target these compounds to deposits of myeloma cells in the bone microenvironment, 2) MMPs produced by the tumor cells will effectively cleave the bisphosphonate to release the "warhead" and achieve more effective concentrations of proteasome inhibitors locally, and 3) the tumor-activated prodrugs will selectively kill tumor cells and prevent or reduce dose-limiting systemic toxicity of pharmaceuticals. The specific aims of the proposal are i) To design and synthesize novel MMP-9 cleavable BP-heptapeptide-PI conjugates as a means of selective delivery of PS-341 to MM cell in bone microenvironment, and ii) To study the proposed compounds in vitro and in vivo. Together, these screens will provide validation for bone-targeted tumor-activated prodrugs as an effective treatment modality for treatment of MM and other bone metastatic cancers.