Development of a first-in-class O-GlcNAc transferase (OGT) inhibitor

化学技术研究人员开发小分子和筛选方法，其他科学家可以用来追求治疗开发的创新。O-GlcNAc转移酶（OGT）是催化O-GlcNAc残基与细胞核和细胞质蛋白质（包括激酶、转录因子、组蛋白和许多其它蛋白质）连接的必需酶，所述蛋白质进而调节许多细胞过程。O-GlcNAc酰化仍然没有得到很好的理解，OGT的小分子抑制剂将成为剖析细胞中这种重要酶功能的关键工具。我们与步行者实验室（哈佛）合作，开发了一种新型小分子OGT抑制剂，并在几种不同的哺乳动物细胞系中验证了其活性，而不影响细胞表面N-或O-连接聚糖的合成。我们正在继续优化这种药物，并正在利用这种OGT生物学探针进行大量合作，以描述其在多种细胞系和疾病环境中的作用。

Chemical Technology researchers develop small molecule and screening approaches that other scientists can use to pursue innovations in therapeutic development. O-GlcNAc transferase (OGT) is an essential enzyme that catalyzes the attachment of O-GlcNAc residues to nuclear and cytoplasmic proteins including kinases, transcription factors, histones and many other proteins which, in turn, regulate numerous cellular processes. O-GlcNAcylation is still not well understood, and small molecule inhibitors of OGT will be a key tool for the dissecting of this important enzymes function in the cell. Working with the Walker lab (Harvard), we have developed a novel small molecule OGT inhibitor and validated its activity in several different mammalian cell lines without affecting synthesis of cell surface N- or O-linked glycans. We are continuing to optimize this agent and are pursuing numerous collaborations using this probe of OGT biology to delineate its role in multiple cell lines and disease settings.