Bone-seeking proteasome inhibitors for myeloma

骨髓瘤寻骨蛋白酶体抑制剂

• 批准号: 7631387
• 负责人: JOSEPH Kofi AGYIN
• 金额: $ 15.32万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7631387
• 关键词: Acids; Address; Adverse effects; Affinity; Animal Model; Animals; Apoptosis; Award; Binding; Biological; Biological Availability; Biology; Bone Marrow; Bone Resorption; Boronic Acids; Cancer Biology; Cells; Chemistry; Clinical Trials; Cytotoxic agent; Deposition; Disease; Doctor of Medicine; Dose-Limiting; Effectiveness; Evaluation; Goals; Growth; Histology; Homing; Hybrids; In Vitro; Label; Lesion; Link; Lytic Metastatic Lesion; MG 262; Malignant Bone Neoplasm; Malignant Neoplasms; Mentors; Methods; Minerals; Modality; Modeling; Multiple Myeloma; Mus; Neoplasms; Organ; Osteogenesis; Patient Agents; Patients; Peptides; Pharmaceutical Preparations; Prodrugs; Property; Proteasome Inhibitor; Refractory; Relapse; Reporting; Safety; Serum; Site; Skeleton; Suppressor Genes; Synthesis Chemistry; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Toxic effect; Tritium; Tumor Burden; Tumor Suppressor Genes; Work; base; bisphosphonate; bone; bone loss; career; cell growth; chemical synthesis; chemotherapeutic agent; clinical remission; design; drug efficacy; effective therapy; human disease; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; interdisciplinary approach; killings; liver function; molecular oncology; neoplastic cell; novel; novel therapeutics; peripheral blood; preclinical evaluation; skills; targeted delivery; tumor

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Standard chemotherapeutic agents have not been effective at significantly prolonging the survival of MM patients and these agents are typically associated with often severe, dose-limiting side effects. 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 K01 proposal is to prepare Dr. Agyin, who has a strong synthetic chemistry background, to develop an independent career focused on the discovery of novel and innovative strategies aimed at selectively delivering therapeutic agents to the bone microenvironment for effective management of MM. In this proposal, the candidate outlines a plan to achieve this objective. Dr. Agyin will acquire skills in cancer and bone biology as they relate primarily to MM and develop a unique strategy to selectively deliver proteasome inhibitors (PS341 and MG262) to bone. Dr. Mundy, a world-renowned expert in myeloma and bone biology will serve as his mentor. Through this award, the candidate will design and synthesize novel PS341- and MG262-Bisphosphonate (PI-BP) conjugates and study their biological effects on MM both in vitro and in vivo. The candidate will also take didactic courses in biology, including Animal Models, Cancer Biology, Oncogenes and Tumor Suppressor Genes, and Molecular Oncology. Our hypothesis is that 1) the linking of bisphosphonates to proteasome inhibitors will target these hybrid compounds to myeloma cells in bone to achieve more effective local concentrations, and 2) that this will effectively kill tumor cells directly at the site of their growth, stimulate bone formation directly at the site of bone loss, and reduce side effects. The specific aims of the proposal are i) To design and synthesize novel PI-BP conjugates as a means of selective delivery of PS341 and MG262 to bone, ii) To synthesize C-14-and C-14/tritium-labeled PS341- and MG262-BP conjugates to study the bioavailability and homing capabilities of the conjugates in vivo, and iii) To study the proposed compounds in vitro and in vivo. The aims of this proposal will be addressed using multidisciplinary approaches including chemical synthesis and biological evaluation. These studies will serve to identify the most promising candidate prodrug to be subsequently tested in clinical trials as a novel treatment modality for MM.

描述(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。标准的化疗药物在显著延长多发性骨髓瘤患者的生存期方面并不有效，而且这些药物通常与严重的、剂量限制的副作用有关。目前迫切需要一种新的、有效的细胞毒剂靶向输送方法，特别是骨髓瘤细胞所在的骨骼。这份K01提案的长期目标是让拥有强大合成化学背景的阿金博士准备好发展一份独立的职业生涯，专注于发现新的和创新的策略，旨在选择性地将治疗剂输送到骨骼微环境，以有效管理MM。在这份提案中，候选人概述了实现这一目标的计划。阿金博士将获得癌症和骨生物学方面的技能，因为它们主要与多发性骨髓瘤有关，并开发一种独特的策略，选择性地将蛋白酶体抑制剂(PS341和MG262)输送到骨中。世界知名的骨髓瘤和骨生物学专家芒迪博士将担任他的导师。通过这一奖项，候选人将设计和合成新颖的PS341-和MG262-双膦酸偶联物(PI-BP)，并研究它们在体外和体内对MM的生物学效应。应聘者还将学习生物学的教学课程，包括动物模型、癌症生物学、癌基因和肿瘤抑制基因以及分子肿瘤学。我们的假设是，1)将双膦酸类化合物与蛋白酶体抑制剂连接起来，将这些杂化化合物靶向骨骼中的骨髓瘤细胞，以实现更有效的局部浓度，以及2)这将有效地在肿瘤细胞生长的部位直接杀死肿瘤细胞，直接在骨丢失部位刺激骨形成，并减少副作用。该方案的具体目的是：i)设计和合成新型PI-BP结合物，作为选择性地将PS341和MG262输送到骨中的手段；ii)合成C-14和C-14/氚标记的PS341-和MG262-BP结合物，以研究这些结合物在体内的生物利用度和归巢能力；以及iii)研究所提出的化合物的体外和体内定位能力。这项提案的目标将采用包括化学合成和生物评价在内的多学科方法来解决。这些研究将有助于确定最有希望的候选前药，随后将在临床试验中作为MM的一种新治疗方式进行测试。