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Novel Potent Autophagy Inhibitors for Melanoma

针对黑色素瘤的新型有效自噬抑制剂

基本信息

批准号：
8589631
负责人：
JEFFREY D WINKLER
金额：
$ 46.51万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-16 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8589631
关键词：
Aminoquinolines Animal Model Antineoplastic Agents Apoptosis Autophagocytosis BRAF gene Binding Cancer Patient Cell Cycle Cell Cycle Arrest Cell Death Cells Chemicals Chloroquine Clinical Trials Combined Modality Therapy Development Distal Drug Combinations Drug Targeting Generations Genetic Genotype Goals Heme Hydroxychloroquine Immunotherapy In Vitro Instruction Investigation Knowledge Lead Libraries Lysosomes Malignant Neoplasms Mammalian Cell Measures Melanoma Cell Metabolic Mitochondria Modeling Molecular Target Neoplasm Metastasis Outcome Patient Selection Patients Pennsylvania Pharmaceutical Preparations Phase I Clinical Trials Play Principal Investigator Process Proteins Proteomics Radiation Role STAT3 gene Signal Transduction Small Interfering RNA Solubility Stress Structure System Testing Therapeutic Transgenic Mice Uncertainty University Hospitals Work Xenograft procedure analog aurora kinase base cancer cell cancer therapy chemotherapeutic agent chemotherapy cytotoxicity design drug candidate drug development in vivo indexing inhibition of autophagy inhibitor/antagonist kinase inhibitor lysosomal proteins mTOR inhibition melanoma novel novel therapeutics overexpression resistance mechanism response scaffold senescence tumor tumor microenvironment

项目摘要

This project is directed toward the development of new chemotherapeutic agents for the treatment of melanoma based on the strategy of autophagy inhibition. Autophagy is an intracellular lysosome-dependent degradative process that protects cancer cells from metabolic and therapeutic stress within the tumor microenvironment. Autophagy inhibition with chloroqulne (CQ) derivatives augments the efficacy of many anticancer therapies, but has limited activity as a single agent therapy despite high levels of autophagy found in most tumors. Numerous clinical trials are testing the combination of variety of anticancer agents witJi hydroxychloroquine (HCQ), an analog of chloroqulne, but concerns have been raised about the potency of HCQ, and its pooriy understood mechanism of action. We have prepared dimeric bisaminoquinoline autophagy inhibitors that are ca. 10x more potent in vitro and in vivo than CQ or HCQ. Our hypothesis is that the new inhibitor LysOS is a more effective inhibitor of a specific unidentified target within the lysosome than standard monovalent CQ derivatives. Our specific aims are: 1) to identify the chemical determinants that characterize the most potent bisaminoquinoline autophagy inhibitors for melanoma cells; 2) to identify the molecular target of LysOS and second-generation bisaminoquinoline autophagy inhibitors in melanoma cells; and 3) to characterize the fates of melanoma cells treated with BAIs, alone and in combination with existing and novel targeted therapies for melanoma. The result of these studies will be the development of potent autophagy inhibitors with known molecular targets and mechanisms of action that will be promising drug development candidates for the treatment of melanoma. RELEVANCE (See instructions): Autophagy is a targetable resistance mechanism to nearly all known anticancer agents, and it plays a particularly important role in melanoma. Currently there are numerous clinical trials testing autophagy inhibition in cancer patients in general and in melanoma patients in particular, coordinated by Dr. Amaravadi at the Hospital of the University of Pennsylvania, employing low potency chloroqulne derivatives as first generation autophagy inhibitors. More potent and targeted autophagy inhibitors are currently unavailable. This proposal is designed to generate a drug candidate based on LysOS, a highly potent bisaminoquinoline autophagy inhibitor that we have developed. Knowledge of the key chemical determinants of effective autophagy inhibition, the molecular target of lysosomotropic aminoquinolines and the antitumor efficacy of these compounds when combined with chemotherapy and targeted therapies will have a significant impact in the field of melanoma chemotherapy. These studies will lead to the development of drug candidates for the treatment of melanoma, with known molecular targets and mechanisms of action; based on the inhibition of autophagy.

本项目旨在开发新的化疗药物，用于治疗黑色素瘤的自噬抑制策略。自噬是一种细胞内溶酶体依赖性的保护癌细胞免受肿瘤内代谢和治疗应激的降解过程微环境氯喹（CQ）衍生物的自噬抑制增强了许多抗肿瘤药物的疗效。抗癌疗法，但作为单一药物治疗的活性有限，尽管发现了高水平的自噬在大多数肿瘤中许多临床试验正在测试各种抗癌药物与Ji的组合。羟氯喹（HCQ），一种氯喹的类似物，但已经提出了关于其效力的担忧。 HCQ，以及其鲜为人知的作用机制。我们已经制备了二聚体双氨基喹啉自噬抑制剂，体外效价提高10倍在体内的作用比CQ或HCQ强。我们的假设是，新的抑制剂LysOS是一种更有效的抑制剂，与标准单价CQ衍生物相比，其在溶酶体内具有特异性未鉴定的靶标。我们的具体目标是：1）确定表征最有效的双氨基喹啉自噬的化学决定簇黑色素瘤细胞的抑制剂; 2）确定LysOS和第二代LysOS的分子靶标黑色素瘤细胞中的双氨基喹啉自噬抑制剂;和3）表征黑色素瘤细胞的命运用BAI单独治疗和与现有的和新的黑素瘤靶向疗法组合治疗的细胞。这些研究的结果将是开发出有效的自噬抑制剂，目标和作用机制，将是有前途的药物开发候选人的治疗黑素瘤相关性（参见说明）：自噬是几乎所有已知抗癌药物的靶向耐药机制，它在肿瘤的治疗中起着重要作用。在黑色素瘤中的作用尤为重要。目前有许多临床试验测试自噬由Amaravadi博士协调，对一般癌症患者，特别是黑色素瘤患者的抑制作用在宾夕法尼亚大学医院，采用低效力氯喹衍生物作为第一个产生自噬抑制剂。目前还没有更有效和更有针对性的自噬抑制剂。该提案旨在产生基于LysOS的候选药物，LysOS是一种高效的双氨基喹啉自噬抑制剂。了解有效的化学决定因素自噬抑制，亲溶酶体氨基喹啉的分子靶点和当这些化合物与化疗和靶向治疗结合时，黑色素瘤化疗领域。这些研究将导致候选药物的开发，用已知的分子靶点和作用机制治疗黑色素瘤;基于抑制自噬