Department Chemie, Center for Integrated Protein Science (CIPSM), Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany.
Current address: Department of Chemistry, Simon Fraser University, Burnaby, Canada.
Chemistry. 2019 Sep 25;25(54):12644-12651. doi: 10.1002/chem.201902919. Epub 2019 Sep 3.
The illudin natural product family are fungal secondary metabolites with a characteristic spirocyclopropyl-substituted fused 6,5-bicyclic ring system. They have been extensively studied for their cytotoxicity in various tumor cell types, and semisynthetic derivatives with improved therapeutic characteristics have progressed to clinical trials. Although it is believed that this potent alkylating compound class acts mainly through DNA modification, little is known about its binding to protein sites in a cellular context. To reveal putative protein targets of the illudin family in live cancer cells, we employed a semisynthetic strategy to access a series of illudin-based probes for activity-based protein profiling (ABPP). While the probes largely retained potent cytotoxicity, proteomic profiling studies unraveled multiple protein hits, suggesting that illudins exert their mode of action not from addressing a specific protein target but rather from DNA modification and unselective protein binding.
抑肽灵天然产物家族是具有特征性螺环丙基取代的稠合 6,5-双环体系的真菌次生代谢产物。它们因其在各种肿瘤细胞类型中的细胞毒性而被广泛研究，并且具有改善治疗特性的半合成衍生物已进入临床试验。尽管人们认为这种强效的烷化化合物主要通过 DNA 修饰起作用，但对于其在细胞环境中与蛋白质结合的情况知之甚少。为了揭示活癌细胞中抑肽灵家族的潜在蛋白质靶标，我们采用半合成策略获得了一系列基于抑肽灵的探针，用于基于活性的蛋白质谱分析 (ABPP)。虽然这些探针在很大程度上保留了有效的细胞毒性，但蛋白质组学分析揭示了多个蛋白质靶点，表明抑肽灵的作用模式不是针对特定的蛋白质靶标，而是来自 DNA 修饰和非选择性的蛋白质结合。
