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. 2012 Nov 12;51(46):11463-7.
doi: 10.1002/anie.201206231. Epub 2012 Oct 12.

Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α

Dennis L Buckley  1 , Jeffrey L Gustafson, Inge Van Molle, Anke G Roth, Hyun Seop Tae, Peter C Gareiss, William L Jorgensen, Alessio Ciulli, Craig M Crews
Affiliations

Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α

Dennis L Buckley et al. Angew Chem Int Ed Engl. .

Abstract

E3 ubiquitin ligases, such as the therapeutically relevant VHL, are challenging targets for traditional medicinal chemistry, as their modulation requires targeting protein-protein interactions. We report novel small-molecule inhibitors of the interaction between VHL and its molecular target HIF1α, a transcription factor involved in oxygen sensing.

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Figures

Figure 1
Figure 1
HIF1α is hydroxylated under normoxic conditions, leading to recognition by VHL followed by ubiquitination and degradation by the proteasome.
Figure 2
Figure 2
Crystal structure of VCB with 24. pVHL is shown in pale green surface representation, the ligand in grey stick representation. pVHL residues forming the binding pocket are shown in yellow stick representation.
Figure 3
Figure 3
Crystal structure of VCB with 51. pVHL is shown in pale green surface representation, the ligand in orange stick representation. pVHL residues forming the binding pocket are shown in yellow stick representation.
See this image and copyright information in PMC

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