Suciu Radu M, Cognetta Armand B, Potter Zachary E, Cravatt Benjamin F
The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, United States.
ACS Med Chem Lett. 2018 May 26;9(6):563-568. doi: 10.1021/acsmedchemlett.8b00191. eCollection 2018 Jun 14.
Wnt proteins are secreted morphogens that play critical roles in embryonic development and tissue remodeling in adult organisms. Aberrant Wnt signaling contributes to diseases such as cancer. Wnts are modified by an unusual -fatty acylation event (-linked palmitoleoylation of a conserved serine) that is required for binding to Frizzled receptors. -Palmitoleoylation of Wnts is introduced by the porcupine (PORCN) acyltransferase and removed by the serine hydrolase NOTUM. PORCN inhibitors are under development for oncology, while NOTUM inhibitors have potential for treating degenerative diseases. Here, we describe the use of activity-based protein profiling (ABPP) to discover and advance a class of -hydroxyhydantoin (NHH) carbamates that potently and selectively inhibit NOTUM. An optimized NHH carbamate inhibitor, ABC99, preserves Wnt-mediated cell signaling in the presence of NOTUM and was also converted into an ABPP probe for visualizing NOTUM in native biological systems.
Wnt蛋白是分泌型形态发生素，在胚胎发育和成年生物体的组织重塑中发挥关键作用。异常的Wnt信号传导会导致癌症等疾病。Wnts通过一种不寻常的脂肪酸酰化事件（保守丝氨酸的O-连接棕榈油酰化）进行修饰，这是与卷曲受体结合所必需的。Wnts的O-棕榈油酰化由刺猬（PORCN）酰基转移酶引入，并由丝氨酸水解酶NOTUM去除。PORCN抑制剂正在开发用于肿瘤学，而NOTUM抑制剂具有治疗退行性疾病的潜力。在这里，我们描述了使用基于活性的蛋白质谱分析（ABPP）来发现和推进一类能有效且选择性抑制NOTUM的O-羟基乙内酰脲（NHH）氨基甲酸酯。一种优化的NHH氨基甲酸酯抑制剂ABC99在存在NOTUM的情况下保留Wnt介导的细胞信号传导，并且还被转化为用于在天然生物系统中可视化NOTUM的ABPP探针。
