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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.

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Galdeano C, Gadd MS, Soares P, Scaffidi S, Van Molle I, Birced I, Hewitt S, Dias DM, Ciulli A
OpenAccess logo J Med Chem 57 8657-63 (2014)
Related entries: 4w9c, 4w9d, 4w9f, 4w9g, 4w9h, 4w9i, 4w9j, 4w9k, 4w9l

Cited: 143 times
EuropePMC logo PMID: 25166285

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.

Articles - 4w9e mentioned but not cited (1)

  1. Discovery of novel inhibitors disrupting HIF-1α/von Hippel-Lindau interaction through shape-based screening and cascade docking. Xue X, Zhao NY, Yu HT, Sun Y, Kang C, Huang QB, Sun HP, Wang XL, Li NG. PeerJ 4 e2757 (2016)


Reviews citing this publication (55)

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Articles citing this publication (87)

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  54. Development of BromoTag: A "Bump-and-Hole"-PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins. Bond AG, Craigon C, Chan KH, Testa A, Karapetsas A, Fasimoye R, Macartney T, Blow JJ, Alessi DR, Ciulli A. J Med Chem 64 15477-15502 (2021)
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