Wang Yue, Zhu Jingjing, Zhang Lianwen
School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences , Beijing 100049, China.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University , Beijing 100191, China.
J Med Chem. 2017 Jan 12;60(1):263-272. doi: 10.1021/acs.jmedchem.6b01237. Epub 2016 Dec 29.
O-GlcNAc transferase (OGT) is a key enzyme involved in dynamic O-GlcNAcylation of nuclear and cytoplasmic proteins similar to phosphorylation. Discovery of cell-permeable OGT inhibitors is significant to clarify the function and regulatory mechanism of O-GlcNAcylation. This will establish the foundation for the development of therapeutic drugs for relevant diseases. Here, we report two cell-permeable OGT inhibitors (APNT and APBT), developed from low-activity precursors (IC > 1 mM) via "tethering in situ click chemistry (TISCC)". Both of them were able to inhibit O-GlcNAcylation in cells without significant effects on cell viability. Unusual noncompetitive inhibition of OGT was helpful to discover novel inhibitors and explore the regulatory mechanism of OGT. The development of these molecules validates that TISCC can be utilized to discover novel lead compounds from components that exhibited very weak binding to the target.
O-连接的N-乙酰葡糖胺转移酶（OGT）是一种关键酶，参与细胞核和细胞质蛋白的动态O-连接的N-乙酰葡糖胺化过程，类似于磷酸化。发现细胞可渗透的OGT抑制剂对于阐明O-连接的N-乙酰葡糖胺化的功能和调节机制具有重要意义。这将为开发相关疾病的治疗药物奠定基础。在此，我们报告了两种细胞可渗透的OGT抑制剂（APNT和APBT），它们是通过“原位连接点击化学（TISCC）”从低活性前体（IC>1 mM）开发而来的。它们都能够抑制细胞中的O-连接的N-乙酰葡糖胺化，而对细胞活力没有显著影响。OGT的异常非竞争性抑制有助于发现新型抑制剂并探索OGT的调节机制。这些分子的开发证实了TISCC可用于从与靶标结合非常弱的成分中发现新型先导化合物。
