School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK.
School of Chemistry, University of East Anglia, Norwich, NR4 7TJ, UK.
Chemistry. 2018 Dec 3;24(67):17677-17680. doi: 10.1002/chem.201804169. Epub 2018 Nov 6.
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.
我们已经专门筛选了小分子文库，以寻找针对 WW P2 的抑制剂，WW P2 是一种与肿瘤生长和扩散相关的 E3 泛素连接酶。选定的化合物显示出剂量依赖性的 WW P2 抑制作用，低微摩尔 IC50 值，并抑制 PTEN 底物特异性泛素化。通过基于配体的 NMR 光谱学证实了与 WW P2 的结合。此外，我们还结合使用 STD NMR、最近开发的 DEEP-STD NMR 方法和对接计算，首次提出了 WW P2-抑制剂复合物的 NMR 验证的三维分子模型。这些第一代 WW P2 抑制剂为提供了一个分子框架，用于指导有机合成方法的改进，以提高活性和选择性。
