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

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。 相关性： 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。

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.