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Discovery of PD-1/PDL-1 inhibitors from marine microbial natural products

从海洋微生物天然产物中发现PD-1/PDL-1抑制剂

基本信息

批准号：
10216205
负责人：
William Fenical
金额：
$ 18.96万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-14 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10216205
关键词：
Antibodies Antineoplastic Agents Aquaculture Bacteria Binding Binding Proteins Biological Biological Assay Biomedical Research Buffers Calorimetry Cancer Biology Cell Line Cell Survival Cells Chemicals China Chinese Hamster Ovary Cell Chinese Traditional Medicine Collection Complex Component of the National Cancer Institute Development Dimethyl Sulfoxide Drug Costs Dyes Evaluation Fermentation Goals Human Immune checkpoint inhibitor Immune system Immunoprecipitation Immunotherapy In Vitro Institution Interferometry Kinetics Lymphocyte Lymphocyte Activation Malignant Neoplasms Measurement Measures Melanoma Cell Modeling Molecular Mus Natural Products Oceanography Oceans PD-1 inhibitors PD-1/PD-L1 Pharmaceutical Preparations Pharmacology Pharmacotherapy Pharmacy Schools Promega Proteins Protocols documentation Rattus Research Personnel Resources Sampling Solid Source Spectrometry, Mass, Electrospray Ionization Structure System T-Cell Activation T-Lymphocyte Techniques Testing Time Titrations Treatment Efficacy United States National Institutes of Health Universities Validation Yin base cancer immunotherapy chemical resource combat deep ocean drug candidate effective therapy experimental study fungus improved inhibitor/antagonist instrumentation large scale production lymphoid neoplasm marine natural product melanoma melting microbial microorganism milligram mouse model novel therapeutics professor programmed cell death ligand 1 programmed cell death protein 1 programs protein protein interaction response screening small molecule small molecule therapeutics tumor growth

项目摘要

Project Summary and Relevance Project Summary: The broad, long-term objective of this collaborative project is the discovery of small molecule therapeutics that can replace antibodies as inhibitors of the PD-1 checkpoint. To date, no small molecules have been approved for this application, although the benefits of small molecules over biologicals in drug therapy is clear. This project capitalizes on the existence of a large collection (up to 30,000 samples) of structurally unique marine microbial metabolites that have shown to be a solid source for the development of anticancer agents. This collection, available at the Scripps Institution of Oceanography, UCSD, from Dr. William Fenical will be interfaced with the cancer biology lab of Dr. Yin Lu at the Nanjing University of Chinese Medicine, to screen for selective inhibitors using a commercially-available cell-based bioassay for PD-1 binding. When active metabolites are discovered, they will be screened in a variety of secondary assays to show selective binding. Finally, verified PD-1binding inhibitors will be produced in multi-milligram amounts by large-scale cultivation and provided to Dr. Lu for evaluation in mouse and rat xenograph models of select cancers. Relevance: This project aims to improve on the immunotherapy of cancer by discovering small molecules that selectively bind to the protein PD-1, which when bound to PDL-1 is responsible for the deactivation of the immune system. Replacing the current antibody (protein) therapy with a small molecule drug is likely to improve treatment efficacy and will clearly reduce drug cost.

项目摘要和相关性项目概要：该合作项目的广泛、长期目标是发现小分子可以替代抗体作为 PD-1 检查点抑制剂的疗法。迄今为止，规模不小分子已被批准用于此应用，尽管小分子的优点药物治疗中生物制剂的优势是显而易见的。该项目利用了大型结构独特的海洋微生物代谢物的集合（最多 30,000 个样本）已被证明是开发抗癌药物的坚实来源。此合集，可用加州大学圣地亚哥分校斯克里普斯海洋学研究所的 William Fenical 博士将进行接口与南京中医药大学陆印博士癌症生物学实验室合作，使用市售的 PD-1 细胞生物测定法筛选选择性抑制剂绑定。当发现活性代谢物时，将在多种二次筛选中进行筛选显示选择性结合的测定。最终，经过验证的 PD-1 结合抑制剂将在通过大规模种植获得数毫克量并提供给卢博士进行评估选定癌症的小鼠和大鼠异种模型。关联：该项目旨在通过发现小分子来改善癌症的免疫疗法选择性地与蛋白质 PD-1 结合，当与 PDL-1 结合时，PD-1 负责免疫系统失活。用抗体（蛋白质）疗法替代当前的抗体（蛋白质）疗法小分子药物可能会提高治疗效果，并明显降低药物成本。