Bone-seeking proteasome inhibitors for myeloma

骨髓瘤寻骨蛋白酶体抑制剂

• 批准号: 7234721
• 负责人: JOSEPH Kofi AGYIN
• 金额: $ 12.84万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7234721
• 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; Clinical Trials; Count; Cytotoxic agent; Deposition; Disease; Disease remission; Doctor of Medicine; Dose-Limiting; Effectiveness; Evaluation; Genes; 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; PS341 cpd; Patient Agents; Patients; Peptides; Pharmaceutical Preparations; Prodrugs; Property; Proteasome Inhibitor; Refractory; Relapse; Reporting; Safety; Serum; Site; Skeleton; Standards of Weights and Measures; Synthesis Chemistry; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Toxic effect; Tritium; Tumor Burden; Tumor Suppressor Genes; United States Food and Drug Administration; Work; base; bisphosphonate; bone; bone loss; boronic acid; career; cell growth; chemical synthesis; chemotherapeutic agent; design; drug efficacy; 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; pre-clinical; 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（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。标准化疗药物在显著延长MM患者的生存期方面并不有效，并且这些药物通常与严重的、剂量限制性副作用相关。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。这个K 01提案的长期目标是准备博士Agyin，谁拥有强大的合成化学背景，发展一个独立的职业生涯，专注于发现新的和创新的策略，旨在选择性地提供治疗药物的骨微环境有效管理MM在这个提案中，候选人概述了一个计划，以实现这一目标。Agyin博士将获得癌症和骨生物学方面的技能，因为它们主要与MM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MG 262）输送到骨骼。世界著名的骨髓瘤和骨生物学专家Mundy博士将担任他的导师。通过该奖项，候选人将设计和合成新型PS341-和MG 262-双膦酸盐（PI-BP）缀合物，并在体外和体内研究其对MM的生物学作用。候选人还将参加生物学教学课程，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）将双膦酸盐与蛋白酶体抑制剂连接将使这些杂合化合物靶向骨中的骨髓瘤细胞，以实现更有效的局部浓度，以及2）这将直接在肿瘤细胞生长部位有效杀死肿瘤细胞，直接在骨丢失部位刺激骨形成，并减少副作用。该提案的具体目的是i）设计和合成新型PI-BP缀合物作为选择性递送PS341和MG 262至骨的手段，ii）合成C-14-和C-14/氚标记的PS341-和MG 262-BP缀合物以研究缀合物在体内的生物利用度和归巢能力，以及iii）在体外和体内研究所提出的化合物。将采用多学科方法，包括化学合成和生物评价，来实现本提案的目标。这些研究将有助于确定最有前途的候选前药，随后在临床试验中作为MM的新治疗方式进行测试。