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Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction

[Image: see text] 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 mo...

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Autores principales: Buckley, Dennis L., Van Molle, Inge, Gareiss, Peter C., Tae, Hyun Seop, Michel, Julien, Noblin, Devin J., Jorgensen, William L., Ciulli, Alessio, Crews, Craig M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2012
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448299/
https://www.ncbi.nlm.nih.gov/pubmed/22369643
http://dx.doi.org/10.1021/ja209924v
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author Buckley, Dennis L.
Van Molle, Inge
Gareiss, Peter C.
Tae, Hyun Seop
Michel, Julien
Noblin, Devin J.
Jorgensen, William L.
Ciulli, Alessio
Crews, Craig M.
author_facet Buckley, Dennis L.
Van Molle, Inge
Gareiss, Peter C.
Tae, Hyun Seop
Michel, Julien
Noblin, Devin J.
Jorgensen, William L.
Ciulli, Alessio
Crews, Craig M.
author_sort Buckley, Dennis L.
collection PubMed
description [Image: see text] 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-1α, 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.
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spelling pubmed-34482992012-09-27 Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction Buckley, Dennis L. Van Molle, Inge Gareiss, Peter C. Tae, Hyun Seop Michel, Julien Noblin, Devin J. Jorgensen, William L. Ciulli, Alessio Crews, Craig M. J Am Chem Soc [Image: see text] 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-1α, 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. American Chemical Society 2012-02-27 2012-03-14 /pmc/articles/PMC3448299/ /pubmed/22369643 http://dx.doi.org/10.1021/ja209924v Text en Copyright © 2012 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.
spellingShingle Buckley, Dennis L.
Van Molle, Inge
Gareiss, Peter C.
Tae, Hyun Seop
Michel, Julien
Noblin, Devin J.
Jorgensen, William L.
Ciulli, Alessio
Crews, Craig M.
Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction
title Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction
title_full Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction
title_fullStr Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction
title_full_unstemmed Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction
title_short Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction
title_sort targeting the von hippel–lindau e3 ubiquitin ligase using small molecules to disrupt the vhl/hif-1α interaction
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448299/
https://www.ncbi.nlm.nih.gov/pubmed/22369643
http://dx.doi.org/10.1021/ja209924v
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