在器官原位培养的人肝细胞和来自肿瘤和正常结肠的患者衍生的器官细胞中对捐赠化学探针(DCP)进行深度注释。
Deep Annotation of Donated Chemical Probes (DCP) in Organotypic Human Liver Cultures and Patient-Derived Organoids from Tumor and Normal Colorectum.
发表日期:2023 Mar 21
作者:
Claudia Tredup, Benardina Ndreshkjana, Natalie S Schneider, Amelie Tjaden, Aurino M Kemas, Sonia Youhanna, Volker M Lauschke, Benedict-Tilman Berger, Andreas Krämer, Lena M Berger, Sandra Röhm, Stefan Knapp, Henner F Farin, Susanne Müller
来源:
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要:
成熟的小分子是研究目标蛋白生物学和治疗相关性的必要工具。然而,文献报道的许多化合物和生物医学研究中常见的化合物缺乏对特定蛋白功能的机制性细胞研究所需的效力和选择性。此外,商业化合物通常不包括行业开发的有用工具,因为它们经常保密。免费提供的化学探针(DCP)库由行业和学术界的慷慨捐赠的化合物推动,便于访问越来越多的这些宝贵和充分描述的工具。本文系统地描述了当前DCP库中的分子集合及其相关的综合描述数据,其中包括多种体外和细胞测定。需要注意的是,我们通过在原代人类肝脏的类囊肿中进行肝毒性筛选以及在患者来源的结直肠癌类器官和匹配的正常邻近上皮中进行细胞存活筛选来表征这一集合。因此,DCP库代表了一个充分描述、公开可用的工具化合物集合,用于研究包括激酶、G蛋白偶联受体和离子通道在内的广泛靶点。作为这样的资源,它为生物医学研究社区提供了独特的资源。
Well-characterized small molecules are essential tools for studying the biology and therapeutic relevance of a target protein. However, many compounds reported in the literature and routinely studied in biomedical research lack the potency and selectivity required for mechanistic cellular studies on the function of a given protein. Furthermore, commercially available compounds often do not include useful tools developed by industry as part of their research and development efforts, as they frequently remain proprietary. The freely available donated chemical probe (DCP) library, fueled by generous donations of compounds from industry and academia, enables easy access to a steadily growing collection of these valuable and well-characterized tools. Here, we provide a systematic description of the current DCP library collection and their associated comprehensive characterization data, including a variety of in vitro and cellular assays. Of note, we characterized the set in relevant human primary models by employing hepatotoxicity screening in primary human liver spheroids and viability screening in patient-derived colorectal cancer organoids and matched normal-adjacent epithelium. Taken together, the DCP library represents a well-annotated, openly available collection of tool compounds for studying a wide range of targets, including kinases, G-protein-coupled receptors, and ion channels. As such, it represents a unique resource for the biomedical research community.