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摘要：这个协作项目的广泛，长期目标是发现小分子可以代替抗体作为PD-1检查点抑制剂的治疗剂。迄今为止，不小尽管小分子的益处在药物治疗中的生物学上很明显。该项目利用了大型的存在收集（最多30,000个样本）结构独特的海洋微生物代谢物，具有被证明是抗癌剂开发的固体来源。这个收藏，可用威廉·菲尼克（William Fenical）博士将在Scripps海洋学研究所，UCSD 在南京大学的Yin Lu博士的癌症生物学实验室中，使用基于市售的细胞生物测定的PD-1的屏幕选择性抑制剂的屏幕结合。当发现活性代谢物时，它们将在各种次级中进行筛选显示选择性绑定的测定。最后，将在大规模种植的多毫克数量，并向LU博士提供评估选择癌症的鼠标和大鼠Xenograph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有选择地结合蛋白质PD-1，当与PDL-1结合时免疫系统停用。用A取代当前抗体（蛋白质）治疗小分子药物可能会提高治疗功效，并明显降低药物成本。