Targeting the von Hippel鈥揕indau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1伪 Interaction

详细信息    查看全文

• 作者：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
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：March 14, 2012
• 年：2012
• 卷：134
• 期：10
• 页码：4465-4468
• 全文大小：284K
• 年卷期：v.134,no.10(March 14, 2012)
• ISSN：1520-5126

文摘

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鈥損rotein interactions. Using rational design, we have generated the first small molecule targeting the von Hippel鈥揕indau 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伪, 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.