Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, U.K.
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K.
J Med Chem. 2020 Apr 9;63(7):3756-3762. doi: 10.1021/acs.jmedchem.0c00144. Epub 2020 Mar 19.
Deubiquitinating enzymes (DUBs) are a growing target class across multiple disease states, with several inhibitors now reported. b-AP15 and VLX1570 are two structurally related USP14/UCH-37 inhibitors. Through a proteomic approach, we demonstrate that these compounds target a diverse range of proteins, resulting in the formation of higher molecular weight (MW) complexes. Activity-based proteome profiling identified CIAPIN1 as a submicromolar covalent target of VLX1570, and further analysis demonstrated that high MW complex formation leads to aggregation of CIAPIN1 in intact cells. Our results suggest that in addition to DUB inhibition, these compounds induce nonspecific protein aggregation, providing molecular explanation for general cellular toxicity.
去泛素化酶（DUBs）是一个在多种疾病状态下不断增长的目标类别，目前已有几种抑制剂被报道。b-AP15 和 VLX1570 是两种结构相关的 USP14/UCH-37 抑制剂。通过蛋白质组学方法，我们证明这些化合物靶向多种不同的蛋白质，导致形成更高分子量（MW）的复合物。基于活性的蛋白质组学分析鉴定出 CIAPIN1 是 VLX1570 的亚毫摩尔共价靶标，进一步的分析表明，MW 复合物的形成导致 CIAPIN1 在完整细胞中的聚集。我们的结果表明，除了 DUB 抑制作用外，这些化合物还诱导非特异性蛋白质聚集，为普遍的细胞毒性提供了分子解释。
