Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, 40225 Düsseldorf, Germany.
Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, 40225 Düsseldorf, Germany.
Bioorg Med Chem. 2019 Dec 1;27(23):115145. doi: 10.1016/j.bmc.2019.115145. Epub 2019 Oct 9.
The therapy of cancer continues to be a challenge aggravated by the evolution of resistance against current medications. As an alternative for the traditional tripartite treatment options of surgery, radiation and chemotherapy, immunotherapy is gaining increasing attention due to the opportunity of more targeted approaches. Promising targets are antigen-presenting cells which drive innate and adaptive immune responses. The discovery and emergence of new drugs and lead structures can be inspired by natural products which comprise many highly bioactive molecules. The development of new drugs based on natural products is hampered by the current lack of guidelines for screening these structures for immune activating compounds. In this work, we describe a phenotypic preclinical screening pipeline for first-line identification of promising natural products using the mouse as a model system. Favorable compounds are defined to be non-toxic to immune target cells, to show direct anti-tumor effects and to be immunostimulatory at the same time. The presented screening pipeline constitutes a useful tool and aims to integrate immune activation in experimental approaches early on in drug discovery. It supports the selection of natural products for later chemical optimization, direct application in in vivo mouse models and clinical trials and promotes the emergence of new innovative drugs for cancer treatment.
癌症的治疗仍然是一个挑战，当前药物的耐药性不断进化，使得这一挑战更加严重。作为手术、放疗和化疗这三种传统三联疗法的替代方案，免疫疗法由于具有更具针对性的治疗机会而受到越来越多的关注。有前途的靶点是抗原呈递细胞，它们可驱动先天和适应性免疫反应。新药和先导结构的发现和出现可以受到天然产物的启发，天然产物包含许多高生物活性的分子。由于目前缺乏筛选这些结构中具有免疫激活化合物的指导方针，基于天然产物的新药的开发受到了阻碍。在这项工作中，我们描述了一种基于表型的临床前筛选管道，用于使用小鼠作为模型系统，对有前途的天然产物进行一线鉴定。有利的化合物被定义为对免疫靶细胞无毒，具有直接的抗肿瘤作用，同时具有免疫刺激作用。所提出的筛选管道是一种有用的工具，旨在在药物发现的早期阶段将免疫激活纳入实验方法中。它支持选择天然产物进行后期化学优化，直接在体内小鼠模型和临床试验中应用，并促进治疗癌症的新型创新药物的出现。
