期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 24, 期 67, 页码 17677-17680出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201804169
关键词
DEEP-STD NMR; drug discovery; ubiquitin ligase; inhibitors; saturation transfer difference NMR
资金
- Prostate Cancer UK [S13-007]
- James Tudor Foundation
- Biotechnology and Biological Sciences Research Council (BBSRC) iCASE PhD Studentship
- School of Pharmacy at the University of East Anglia (UEA)
- BBSRC [BB/P010660/1]
- Charnwood Molecular Ltd.
- BBSRC [BB/P010660/1, 1644180, 1654460] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/P010660/1] Funding Source: researchfish
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据