Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities.

Galdeano, Carles and Gadd, Morgan Stuart and Soares, Pedro and Scaffidi, Salvatore and van Molle, Inge and Birced, Ipek and Hewitt, Sarah and Dias, David M and Ciulli, Alessio (2014) Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities. Journal of Medicinal Chemistry, 57 (20). pp. 8657-8663. ISSN 0022-2623

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Abstract

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α 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.

Item Type:
Journal Article
Journal or Publication Title:
Journal of Medicinal Chemistry
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1313
Subjects:
ID Code:
89188
Deposited By:
Deposited On:
14 Dec 2017 09:18
Refereed?:
Yes
Published?:
Published
Last Modified:
24 Sep 2020 03:41