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

被引：434

作者：

Buckley, Dennis L. ^{[2
]}

Van Molle, Inge ^{[1
]}

Gareiss, Peter C. ^{[3
]}

Tae, Hyun Seop ^{[3
]}

Michel, Julien ^{[2
]}

Noblin, Devin J. ^{[3
]}

Jorgensen, William L. ^{[2
]}

Ciulli, Alessio ^{[1
]}

Crews, Craig M. ^{[2
,3
,4
]}

机构：

[1] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

[2] Yale Univ, Dept Chem, New Haven, CT 06511 USA

[3] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06511 USA

[4] Yale Univ, Dept Pharmacol, New Haven, CT 06511 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2012年 / 134卷 / 10期

基金：

英国生物技术与生命科学研究理事会;

关键词：

HYDROXYPROLINE; RECOGNITION; INHIBITORS; DISCOVERY; CANCER; POTENT; ANTAGONISTS; PROTEASOME; DISEASE; COMPLEX;

D O I：

10.1021/ja209924v

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

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-1 alpha, 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.

引用

页码：4465 / 4468

页数：4

共 28 条

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Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids [J].