Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors,Chemistry - A European Journal

当前位置： X-MOL 学术 › Chem. Eur. J. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors
Chemistry - A European Journal ( IF 3.9 ) Pub Date : 2018-11-06 , DOI: 10.1002/chem.201804169
Jessica E. Watt ₁ , Gregory R. Hughes _{1,

2} , Samuel Walpole ₃ , Serena Monaco ₃ , G. Richard Stephenson ₂ , Philip C. Bulman Page ₂ , Andrew M. Hemmings _{1,

2} , Jesus Angulo ₃ , Andrew Chantry ₁

Affiliation

We have screened small molecule libraries specifically for inhibitors that target WWP2, an E3 ubiquitin ligase associated with tumour outgrowth and spread. Selected hits demonstrated dose‐dependent WWP2 inhibition, low micromolar IC50 values, and inhibition of PTEN substrate‐specific ubiquitination. Binding to WWP2 was confirmed by ligand‐based NMR spectroscopy. Furthermore, we used a combination of STD NMR, the recently developed DEEP‐STD NMR approach, and docking calculations, to propose for the first time an NMR‐validated 3D molecular model of a WWP2‐inhibitor complex. These first generation WWP2 inhibitors provide a molecular framework for informing organic synthetic approaches to improve activity and selectivity.

中文翻译：

小分子WWP2泛素连接酶抑制剂的发现

我们筛选了专门针对靶向WWP2的抑制剂的小分子文库，WWP2是与肿瘤生长和扩散相关的E3泛素连接酶。选定的命中样品显示出剂量依赖性的WWP2抑制，低微摩尔IC50值和PTEN底物特异性泛素化抑制。通过基于配体的NMR光谱证实了与WWP2的结合。此外，我们结合使用了STD NMR，最近开发的DEEP-STD NMR方法和对接计算，首次提出了WWP2-抑制剂复合物的NMR验证的3D分子模型。这些第一代WWP2抑制剂提供了分子框架，可为有机合成方法提供信息，以改善活性和选择性。

更新日期：2018-11-06

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文