Galdeano Carles, Gadd Morgan S, Soares Pedro, Scaffidi Salvatore, Van Molle Inge, Birced Ipek, Hewitt Sarah, Dias David M, Ciulli Alessio
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee, DD1 5EH, Scotland, U.K.
J Med Chem. 2014 Oct 23;57(20):8657-63. doi: 10.1021/jm5011258. Epub 2014 Oct 6.
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-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α 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.
E3泛素连接酶是泛素-蛋白酶体系统中颇具吸引力的靶点，然而，小分子配体的研发成果有限。冯·希佩尔-林道蛋白（pVHL）是VHL E3连接酶的底物识别亚基，可靶向降解缺氧诱导因子-1α（HIF-1α）。我们最近报道了pVHL:HIF-1α相互作用的抑制剂，但它们的活性中等。在此，我们报告了在X射线晶体结构指导下设计和优化的一系列具有纳摩尔结合亲和力的配体。
