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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

基本信息

批准号：
9311497
负责人：
Arthur G Roberts
金额：
$ 36.32万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
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/9311497
关键词：
ATP Hydrolysis Adverse effects Anthracyclines 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 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 therapy chemotherapy design drug development drug efficacy expectation extracellular functional group improved in vivo inhibitor/antagonist innovation molecular transporter mortality multidrug transport mutant novel tumor

项目摘要

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.

抗癌药物抗性肿瘤代表了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多药耐药1（MDR 1）反式- 波特，它流出一个相对广泛的抗癌药物，并已确定在约50%的恶性肿瘤尽管许多研究发现，抗癌药物-转运蛋白相互作用并且它们的分子转运机制目前还不清楚。扩大我们的- 从MDR 1的抗癌药物转运来看，迫切需要定义分子和抗癌药物转运的结构基础。我们建议进行的研究的整体目标，是界定抗癌药物转运的分子机制，确定抗癌药物功能基团与转运蛋白相互作用并精确定位MDR 1上的抗癌药物结合位点传送器基于已知的小鼠mdr 3转运蛋白的X射线晶体结构，一种假说是，人MDR 1的抗癌药物转运速率受多种药物控制与转运蛋白的细胞外侧紧密结合（靠近Y 953）。从这个中心假设，提出了两个具体的目标：第一个具体的目标是定义的机制，通过MDR 1的癌症药物转运，并检验抗癌药物转运率是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MDR 1构象，利用核磁共振技术确定抗癌药物在MDR 1上的位置。这些调查已被... 签署以检验具有更高转运率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，成功完成了这些研究将导致识别导致MDR 1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的第四代MDR 1反式- 转运蛋白抑制剂，并对候选的和市售的抗- 癌症药物，以尽量减少MDR 1介导的外流。如果没有新的知识，从完成这项研究，合理设计药物的有效策略，可以有效地克服MDR 1- 介导的癌症耐药性可能仍然有限，而MDR 1介导的耐药性将重新出现。主要是癌症耐药性和死亡率的主要原因。