Artigo Acesso aberto Revisado por pares

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

2014; American Chemical Society; Volume: 57; Issue: 20 Linguagem: Inglês

10.1021/jm5011258

ISSN

1520-4804

Autores

Carles Galdeano, Morgan S. Gadd, Pedro Soares, Salvatore Scaffidi, Inge Van Molle, Ipek Birced, Sarah H. Hewitt, David M. Dias, Alessio Ciulli,

Tópico(s)

Protein Degradation and Inhibitors

Resumo

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.

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