Selective Irreversible Inhibitors of the Wnt-Deacylating Enzyme NOTUM Developed by Activity-Based Protein Profiling,ACS Medicinal Chemistry Letters

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Selective Irreversible Inhibitors of the Wnt-Deacylating Enzyme NOTUM Developed by Activity-Based Protein Profiling
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-05-26 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00191
Radu M. Suciu ₁ , Armand B. Cognetta ₁ , Zachary E. Potter ₁ , Benjamin F. Cravatt ₁

Affiliation

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 O-fatty acylation event (O-linked palmitoleoylation of a conserved serine) that is required for binding to Frizzled receptors. O-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 N-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.

中文翻译：

通过基于活动的蛋白谱分析开发的Wnt去酰化酶NOTUM的选择性不可逆抑制剂

Wnt蛋白是分泌的形态发生子，在成年生物的胚胎发育和组织重塑中起关键作用。Wnt信号异常会导致癌症等疾病。Wnts通过与Frizzled受体结合所需的异常O脂肪酸酰化事件（保守丝氨酸的O联棕榈油酰化）进行修饰。豪猪（PORCN）酰基转移酶引入Wnts的O-棕榈油酰化作用，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，我们描述了基于活动的蛋白质谱分析（ABPP）的使用，以发现和促进一类N-羟基乙内酰脲（NHH）氨基甲酸酯能有效和选择性地抑制NOTUM。优化的NHH氨基甲酸酯抑制剂ABC99在NOTUM存在的情况下保留Wnt介导的细胞信号转导，并且还转化为ABPP探针，用于在天然生物系统中可视化NOTUM。

更新日期：2018-05-26

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