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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：
10669189
负责人：
William Fenical
金额：
$ 18.58万
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/10669189
关键词：
Antibodies Antineoplastic Agents Aquaculture Bacteria Binding Binding Proteins Biological Assay Biomedical Research Buffers Calorimetry Cancer Biology Cell Line Cell Survival Cells Chemicals China Chinese Hamster Ovary Cell Chinese Traditional Medicine Collaborations 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 antagonist cancer immunotherapy chemical resource combat deep ocean drug candidate effective therapy experimental study fungus improved inhibitor instrumentation large scale production marine marine natural product melanoma melting microbial microorganism milligram mouse model novel therapeutics professor programmed cell death ligand 1 programmed cell death protein 1 programs 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：这个合作项目的广泛的长期目标是发现小分子可以替代抗体作为PD-1检查点抑制剂的治疗剂。迄今为止，分子已经被批准用于该应用，尽管小分子的益处药物治疗中的生物制剂是显而易见的。该项目利用了一个大型的收集（多达30 000个样品）结构独特的海洋微生物代谢物，显示为开发抗癌剂的固体来源。此系列，可用在斯克里普斯海洋学研究所，加州大学圣地亚哥分校，从博士威廉Fenical将接口与南京中医药大学的尹璐博士的癌症生物学实验室合作，使用市售的基于细胞的PD-1生物测定筛选选择性抑制剂约束力当活性代谢产物被发现时，它们将在各种次级代谢产物中被筛选。分析以显示选择性结合。最后，验证PD-1结合抑制剂将在通过大规模培养获得了数毫克的量，并提供给陆博士进行评估，选择癌症的小鼠和大鼠异种移植模型。相关性：该项目旨在通过发现小分子来改善癌症的免疫治疗选择性结合蛋白PD-1，当结合PDL-1时，负责免疫系统的失活。用抗体（蛋白质）替代目前的抗体（蛋白质）治疗。小分子药物有可能提高治疗效果并将明显降低药物成本。