Structure-Guided Design and Optimization of Small Molecules Targeting the Protein鈥揚rotein Interaction between the von Hippel鈥揕indau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alp
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- 作者：Carles Galdeano ; Morgan S. Gadd ; Pedro Soares ; Salvatore Scaffidi ; Inge Van Molle ; Ipek Birced ; Sarah Hewitt ; David M. Dias ; Alessio Ciulli
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：October 23, 2014
- 年：2014
- 卷：57
- 期：20
- 页码：8657-8663
- 全文大小：448K
- ISSN：1520-4804
文摘
E3 ubiquitin ligases are attractive targets in the ubiquitin鈥損roteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel鈥揕indau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1伪 for degradation. We recently reported inhibitors of the pVHL:HIF-1伪 interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.