Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction

Dennis L. Buckley, Inge Van Molle, Peter C. Gareiss, Hyun Seop Tae, Julien Michel, Devin J. Noblin, William L. Jorgensen, Alessio Ciulli, Craig M. Crews

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    169 Citations (Scopus)

    Abstract

    E3 ubiquitin ligases, which bind protein targets, leading to their ubiquitination and subsequent degradation, are attractive drug targets due to their exquisite substrate specificity. However, the development of small-molecule inhibitors has proven extraordinarily challenging as modulation of E3 ligase activities requires the targeting of protein-protein interactions. Using rational design, we have generated the first small molecule targeting the von Hippel-Lindau protein (VHL), the substrate recognition subunit of an E3 ligase, and an important target in cancer, chronic anemia, and ischemia. We have also obtained the crystal structure of VHL bound to our most potent inhibitor, confirming that the compound mimics the binding mode of the transcription factor HIF-1a, a substrate of VHL. These results have the potential to guide future development of improved lead compounds as therapeutics for the treatment of chronic anemia and ischemia.
    Original languageEnglish
    Pages (from-to)4465-4468
    Number of pages4
    JournalJournal of the American Chemical Society
    Volume134
    Issue number10
    DOIs
    Publication statusPublished - 2012

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  • Cite this

    Buckley, D. L., Van Molle, I., Gareiss, P. C., Tae, H. S., Michel, J., Noblin, D. J., Jorgensen, W. L., Ciulli, A., & Crews, C. M. (2012). Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction. Journal of the American Chemical Society, 134(10), 4465-4468. https://doi.org/10.1021/ja209924v