Details

Autor(en) / Beteiligte

• Soares, Pedro
• Gadd, Morgan S
• Frost, Julianty
• Galdeano, Carles
• Ellis, Lucy
• Epemolu, Ola
• Rocha, Sonia
• Read, Kevin D
• Ciulli, Alessio

Titel

Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel–Lindau (VHL) E3 Ubiquitin Ligase: Structure–Activity Relationships Leading to the Chemical Probe (2S,4R)‑1-((S)‑2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy‑N‑(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298)

Ist Teil von

• Journal of medicinal chemistry, 2018-01, Vol.61 (2), p.599-618

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• The von Hippel–Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein–protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure–activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways and new VHL ligands for next-generation PROTACs.