Evotec SE, Essener Bogen 7, 22419 Hamburg, Germany.
Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany.
Drug Discov Today Technol. 2020 Dec;37:73-82. doi: 10.1016/j.ddtec.2020.11.005. Epub 2020 Dec 10.
Small molecule induced protein degradation has created tremendous excitement in drug discovery within recent years. Not being confined to target inhibition and being able to remove disease-causing protein targets via engagement and subsequent ubiquitination has provided scientists with a powerful tool to expand the druggable space. At the center of this approach sits the ternary complex formed between an E3 ubiquitin ligase, the small molecule degrader, and the target protein. A productive ternary complex is pivotal for a ubiquitin to be transferred to a surface lysine of the target protein resulting in poly-ubiquitination which enables recognition and finally degradation by the proteasome. As understanding the ternary complex means understanding the degradation process, many efforts are put into obtaining structural information of the ternary complex and getting a snapshot of the underlying conformations and molecular contacts. Locking this transient trimeric intermediate in a crystalline state has proven to be very demanding but the obtained results have tremendously improved our understanding of small molecule degraders. This review discusses target protein degradation from a structural perspective and highlights the evolution of certain degraders based on the obtained structural insights.
近年来，小分子诱导的蛋白质降解在药物发现领域引起了极大的关注。这种方法不受限于靶标抑制，并且能够通过结合和随后的泛素化来去除致病蛋白靶标，为科学家提供了一种扩展可成药靶点的强大工具。这种方法的核心是由 E3 泛素连接酶、小分子降解剂和靶蛋白形成的三元复合物。一个有效的三元复合物对于将泛素转移到靶蛋白表面赖氨酸上至关重要，从而导致多泛素化，使靶蛋白被蛋白酶体识别并最终降解。由于理解三元复合物意味着理解降解过程，因此人们投入了大量精力来获得三元复合物的结构信息，并获取潜在构象和分子接触的快照。将这种短暂的三聚体中间物锁定在晶体状态非常具有挑战性，但获得的结果极大地提高了我们对小分子降解剂的理解。本文从结构角度讨论了靶蛋白的降解，并根据获得的结构见解强调了某些降解剂的演变。
