Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany; TU Dortmund University, Emil-Figge-Str. 72, 44221 Dortmund, Germany; RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany; RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Cell Chem Biol. 2021 Jun 17;28(6):848-854.e5. doi: 10.1016/j.chembiol.2021.01.009. Epub 2021 Feb 9.
Phenotypic screening for bioactive small molecules is typically combined with affinity-based chemical proteomics to uncover the respective molecular targets. However, such assays and the explored bioactivity are biased toward the monitored phenotype, and target identification often requires chemical derivatization of the hit compound. In contrast, unbiased cellular profiling approaches record hundreds of parameters upon compound perturbation to map bioactivity in a broader biological context and may link a profile to the molecular target or mode of action. Herein we report the discovery of the diaminopyrimidine DP68 as a Sigma 1 (σ) receptor antagonist by combining morphological profiling using the Cell Painting assay and thermal proteome profiling. Our results highlight that integration of complementary profiling approaches may enable both detection of bioactivity and target identification for small molecules.
表型筛选通常与基于亲和力的化学蛋白质组学相结合，以揭示相应的分子靶标。然而，此类测定和所探索的生物活性偏向于所监测的表型，并且靶标鉴定通常需要对命中化合物进行化学衍生化。相比之下，无偏细胞分析方法在化合物扰动时记录数百个参数，以在更广泛的生物学背景下绘制生物活性，并可将图谱与分子靶标或作用模式相关联。在此，我们报告了通过结合使用细胞染色测定的形态分析和热蛋白质组学分析，发现二氨基嘧啶 DP68 是 Sigma 1 (σ)受体拮抗剂。我们的结果强调，互补分析方法的整合可同时检测小分子的生物活性和靶标鉴定。
