靶向蛋白降解技术的开发之路

靶向蛋白降解是当前热门的化学敲除工具和新药研发策略。与传统小分子抑制剂相比，靶向蛋白降解技术利用机体固有的蛋白清除机制（如泛素-蛋白酶体系统或溶酶体途径）特异性降解致病目标蛋白，在降低毒副作用、克服耐药，以及靶向难成药靶点等方面具有突出优势。本文结合笔者团队的相关研究，聚焦多种新兴的靶向蛋白降解技术，例如PROTAC、分子胶、LYTAC、ATTEC、AUTAC和 AUTOTAC等，分析靶向蛋白降解技术的应用前景和未来发展趋势。

Advances in targeted protein degradation

Targeted protein degradation (TPD) is emerging as a promising strategy for chemical knockdown and drug discovery. TPD strategies eliminate specific disease-associated proteins by hijacking the intracellular proteolysis machinery, including the ubiquitin–proteasome system or the lysosomal degradation pathway. Compared to traditional small-molecular inhibitors, TPD strategies have not only exhibited significant advantages in reducing toxic side effects and the risk of drug resistance, but also further broadened the target space including many “undruggable” proteins. Inspired by the related studies of our group in the field of TPD, we will summarize recent advances of major TPD technologies (e.g. PROTAC, molecular glue, LYTAC, ATTEC, AUTAC and AUTOTAC), and discuss their potential applications and developing trend.