Deep Annotation of Donated Chemical Probes (DCP) in Organotypic Human Liver Cultures and Patient-Derived Organoids from Tumor and Normal Colorectum

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.

经过充分表征的小分子是研究靶蛋白生物学特性及其治疗相关性的核心工具。然而，文献中报道的、生物医学研究中常规使用的诸多化合物，并不具备研究特定蛋白功能所需的机制性细胞实验所要求的效力与选择性。此外，市售化合物往往未收录工业界在研发过程中开发的实用工具分子，因为这类分子通常属于专有范畴。由工业界与学术界慷慨捐赠化合物构建的免费开放捐赠化学探针（Donated Chemical Probe Library, DCP）库，为科研人员提供了便捷获取不断扩充的高价值、经充分表征工具分子集合的途径。

本文系统阐述了当前DCP库的收录情况，以及与之配套的全面表征数据，涵盖多种体外实验与细胞检测实验。值得注意的是，本研究通过在原代人肝脏球状体中开展肝毒性筛选、在患者来源结直肠癌类器官及其配对癌旁正常上皮组织中开展细胞活力筛选，在相关人类原代模型中完成了该探针库的表征工作。

综上，DCP库是一套注释完善、公开可及的工具化合物集合，可用于研究包括激酶、G蛋白偶联受体与离子通道在内的众多靶标，是面向生物医学科研界的独特宝贵资源。