Document Report Card

ID: ALA3351366

Journal: J Med Chem

Title: 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.

Authors: Galdeano C, Gadd MS, Soares P, Scaffidi S, Van Molle I, Birced I, Hewitt S, Dias DM, Ciulli A.

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.

CiteXplore: 25166285

DOI: 10.1021/jm5011258