Zhang Yi, Loh Christine, Chen Jesse, Mainolfi Nello
Kymera Therapeutics, 300 Technology Square, Cambridge, MA, 02139, USA.
Kymera Therapeutics, 300 Technology Square, Cambridge, MA, 02139, USA.
Drug Discov Today Technol. 2019 Apr;31:53-60. doi: 10.1016/j.ddtec.2019.01.001. Epub 2019 Jan 28.
Targeted protein degradation mediated by small molecule degraders represents an exciting new therapeutic opportunity to eliminate disease-causing proteins. These molecules recruit E3 ubiquitin ligases to the protein of interest and mediate its ubiquitination and subsequent proteolysis by the proteasome. Significant advancements have been made in the discovery and development of clinically relevant degraders. In this review we will focus on the recent progress in understanding ternary complex formation and structures, ubiquitination, and other critical factors that govern the efficiency of degraders both in vitro and in vivo. With deeper knowledges of these areas, the field is building guiding principles to reduce the level of empiricism and to identify therapeutically relevant degraders more rationally and efficiently.
由小分子降解剂介导的靶向蛋白质降解为消除致病蛋白提供了一个令人兴奋的新治疗机会。这些分子将E3泛素连接酶招募到目标蛋白上，并介导其泛素化以及随后被蛋白酶体进行蛋白水解。在临床相关降解剂的发现和开发方面已经取得了重大进展。在这篇综述中，我们将重点关注在理解三元复合物形成和结构、泛素化以及其他在体外和体内决定降解剂效率的关键因素方面的最新进展。随着对这些领域更深入的了解，该领域正在建立指导原则，以减少经验主义程度，并更合理、高效地识别具有治疗相关性的降解剂。
