Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.
J Am Chem Soc. 2012 Mar 14;134(10):4465-8. doi: 10.1021/ja209924v. Epub 2012 Feb 27.
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-1α, 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.
E3 泛素连接酶可与蛋白质靶标结合，导致其泛素化和随后的降解，由于其出色的底物特异性，它们成为有吸引力的药物靶点。然而，由于调节 E3 连接酶活性需要靶向蛋白质-蛋白质相互作用，因此开发小分子抑制剂被证明极具挑战性。我们通过合理设计，生成了第一个针对 von Hippel-Lindau 蛋白（VHL）的小分子，VHL 是 E3 连接酶的底物识别亚基，也是癌症、慢性贫血和缺血的重要靶点。我们还获得了 VHL 与我们最有效的抑制剂结合的晶体结构，证实该化合物模拟了 VHL 的底物转录因子 HIF-1α的结合模式。这些结果有可能指导未来开发出改进的先导化合物，作为治疗慢性贫血和缺血的药物。
