期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 20, 页码 8657-8663出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm5011258
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资金
- UK Biotechnology and Biological Sciences Research Council [BBSRC BB/G023123/1]
- European Research Council [ERC-2012-StG-311460 DrugE3CRLs]
- EC [PIEF-GA-2012-328030, PIEF-GA-2010-275683]
- Fundacao para a Ciencia e a Tecnologia (FCT) [SFRH/BD/81735/2011]
- Wellcome Trust [100476/Z/12/Z, 094090/Z/10/Z]
- Italian Ministry of Education, University and Research (MIUR) [497]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/81735/2011] Funding Source: FCT
- Biotechnology and Biological Sciences Research Council [BB/G023123/2, BB/G023123/1] Funding Source: researchfish
- BBSRC [BB/G023123/1, BB/G023123/2] Funding Source: UKRI
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-1a for degradation. We recently reported inhibitors of the pVHL:HIF-1 alpha 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.
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