Overcoming Cancer Resistance Mediated by the Human MDR1 Transporter

克服人类 MDR1 转运蛋白介导的癌症抵抗力

• 批准号: 9982821
• 负责人: Arthur G Roberts
• 金额: $ 40.35万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982821
• 关键词: ATP Hydrolysis; Anthracycline; Antineoplastic Agents; Atomic Force Microscopy; Binding; Binding Sites; Cancer Etiology; Cancerous; Chemicals; Coupling; Crystallization; Development; Drug Binding Site; Drug Delivery Systems; Drug Design; Drug Efflux; Drug Interactions; Drug Transport; Drug resistance; Drug toxicity; Generations; Goals; Human; Hydrophobicity; In Vitro; Investigation; Knowledge; Lead; Ligands; Location; Malignant Neoplasms; Mediating; Metabolic Pump; Modification; Molecular; Molecular Conformation; Molecular Structure; Multi-Drug Resistance; Mus; Outcome; P-Glycoprotein; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Property; Research; Resistance; Roentgen Rays; Role; Side; Specificity; Structure; Taxoids; Testing; Time; Transport Process; Vinca Alkaloids; base; cancer drug resistance; cancer therapy; chemotherapy; design; drug development; drug efficacy; expectation; extracellular; functional group; improved; in vivo; inhibitor/antagonist; innovation; molecular transporter; mortality; multidrug transport; mutant; novel; side effect; tumor

Anti-cancer drug-resistant tumors represent a major impediment to effective cancer therapy. One of the main pathways of cancer resistance is through the human multidrug resistance 1 (MDR1) trans- porter, which effluxes a relatively broad range of anti-cancer drugs and has been identified in ~50% of cancerous tumors. Despite findings from numerous studies, anti-cancer drug-transporter interactions and their molecular transport mechanisms are currently not well understood. To broaden our under- standing of anti-cancer drug transport by MDR1, there is a critical need to define the molecular and structural basis of anti-cancer drug transport. Our overall objective in the proposed studies is to define the molecular mechanisms of anti-cancer drug transport, to identify anti-cancer drug functional groups that interact with the transporter and to pinpoint the anti-cancer drug binding sites on the MDR1 transporter. Based on the known X-ray crystal structure of the mouse mdr3 transporter, the central hypothesis is that the anti-cancer drug transport rate by human MDR1 is controlled by multiple drugs binding in close proximity to the extracellular side of the transporter (near Y953). From this central hypothesis, two specific aims are proposed: The first specific aim is to define the mechanism of anti- cancer drug transport by MDR1 and to test the hypothesis that the anti-cancer drug transport rate is directly related to the number of anti-cancer drug binding sites. The second specific aim is to deter- mine the anti-cancer drug bound MDR1 conformations using atomic force microscopy (AFM) and to pinpoint the locations of anti-cancer drugs on MDR1 by NMR. These investigations have been de- signed to test the hypothesis that anti-cancer drugs with higher transport rates have binding sites relatively close to the extracellular side of the transporter. Ultimately, the successful completion of these studies will lead to the identification of specific anti-cancer drug properties that lead to MDR1- mediated transport. This information will allow us to design of novel fourth generation MDR1 trans- porter inhibitors and to make rational modifications of candidate and commercially available anti- cancer drugs to minimize MDR1-mediated efflux. Without the new knowledge from the completion of this research, effective strategies for rationally designing drugs that can effectively overcome MDR1- mediated cancer resistance are likely to remain limited and MDR1-mediated drug resistance will re- main a leading cause of cancer resistance and mortality.

抗癌药物耐药性肿瘤是有效癌症治疗的主要障碍。之一 癌症耐药的主要途径是通过人类多药耐药1（MDR1）反式 波特，它流出相对广泛的抗癌药物，并已在约 50% 的癌症中被发现 癌性肿瘤。尽管大量研究发现，抗癌药物转运蛋白相互作用 其分子运输机制目前尚不清楚。为了扩大我们的范围 鉴于 MDR1 抗癌药物转运的地位，迫切需要定义分子和 抗癌药物转运的结构基础。我们拟议研究的总体目标是定义 抗癌药物转运的分子机制，鉴定抗癌药物功能基团 与转运蛋白相互作用并精确定位 MDR1 上的抗癌药物结合位点 运输者。基于已知的小鼠 mdr3 转运蛋白的 X 射线晶体结构，中央 假设人类 MDR1 的抗癌药物转运速率是由多种药物控制的 与转运蛋白的细胞外侧（靠近 Y953）结合。从这个中央 假设，提出了两个具体目标：第一个具体目标是定义反作用机制 MDR1 的癌症药物转运并检验抗癌药物转运率的假设 与抗癌药物结合位点的数量直接相关。第二个具体目标是阻止 使用原子力显微镜 (AFM) 挖掘抗癌药物结合的 MDR1 构象并 通过 NMR 精确定位抗癌药物在 MDR1 上的位置。这些调查已被取消 签署以检验转运率较高的抗癌药物具有结合位点的假设 相对靠近转运蛋白的细胞外侧。最终顺利完成 这些研究将确定导致 MDR1- 的特定抗癌药物特性 介导的运输。这些信息将使我们能够设计新颖的第四代 MDR1 反式 波特抑制剂并对候选和市售抗- 抗癌药物可最大限度地减少 MDR1 介导的外排。没有从完成中获得新的知识 这项研究提出了合理设计能够有效克服MDR1-的药物的有效策略 介导的癌症耐药性可能仍然有限，而 MDR1 介导的耐药性将重新出现 主要是癌症抵抗和死亡的主要原因。