Ortiz-Meoz Rodrigo F, Jiang Jiaoyang, Lazarus Michael B, Orman Marina, Janetzko John, Fan Chenguang, Duveau Damien Y, Tan Zhi-Wei, Thomas Craig J, Walker Suzanne
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
‡National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States.
ACS Chem Biol. 2015 Jun 19;10(6):1392-7. doi: 10.1021/acschembio.5b00004. Epub 2015 Mar 18.
O-GlcNAc transferase (OGT) is an essential mammalian enzyme that regulates numerous cellular processes through the attachment of O-linked N-acetylglucosamine (O-GlcNAc) residues to nuclear and cytoplasmic proteins. Its targets include kinases, phosphatases, transcription factors, histones, and many other intracellular proteins. The biology of O-GlcNAc modification is still not well understood, and cell-permeable inhibitors of OGT are needed both as research tools and for validating OGT as a therapeutic target. Here, we report a small molecule OGT inhibitor, OSMI-1, developed from a high-throughput screening hit. It is cell-permeable and inhibits protein O-GlcNAcylation in several mammalian cell lines without qualitatively altering cell surface N- or O-linked glycans. The development of this molecule validates high-throughput screening approaches for the discovery of glycosyltransferase inhibitors, and further optimization of this scaffold may lead to yet more potent OGT inhibitors useful for studying OGT in animal models.
O-连接的N-乙酰葡糖胺转移酶（OGT）是一种重要的哺乳动物酶，它通过将O-连接的N-乙酰葡糖胺（O-GlcNAc）残基连接到核蛋白和细胞质蛋白上来调节众多细胞过程。其作用靶点包括激酶、磷酸酶、转录因子、组蛋白以及许多其他细胞内蛋白。O-GlcNAc修饰的生物学机制仍未完全阐明，因此既需要细胞可渗透的OGT抑制剂作为研究工具，也需要其来验证OGT作为治疗靶点的可行性。在此，我们报道了一种从小分子高通量筛选命中物开发而来的OGT抑制剂——OSMI-1。它具有细胞渗透性，能在几种哺乳动物细胞系中抑制蛋白质O-GlcNAc化，且不会定性改变细胞表面的N-连接或O-连接聚糖。该分子的开发验证了高通量筛选方法在发现糖基转移酶抑制剂方面的有效性，对该骨架的进一步优化可能会产生更有效的OGT抑制剂，有助于在动物模型中研究OGT。
