State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
EBioMedicine. 2018 Oct;36:553-562. doi: 10.1016/j.ebiom.2018.09.005. Epub 2018 Sep 14.
There are several challenges towards the development and clinical use of small molecule inhibitors, which are currently the main type of targeted therapies towards intracellular proteins. PROteolysis-TArgeting Chimeras (PROTACs) exploit the intracellular ubiquitin-proteasome system to selectively degrade target proteins. Recently, small-molecule PROTACs with high potency have been frequently reported. In this review, we summarize the emerging characteristics of small-molecule PROTACs, such as inducing a rapid, profound and sustained degradation, inducing a robust inhibition of downstream signals, displaying enhanced target selectivity, and overcoming resistance to small molecule inhibitors. In tumor xenografts, small-molecule PROTACs can significantly attenuate tumor progression. In addition, we also introduce recent developments of the PROTAC technology such as homo-PROTACs. The outstanding advantages over traditional small-molecule drugs and the promising preclinical data suggest that small-molecule PROTAC technology has the potential to greatly promote the development of targeted therapy drugs.
小分子抑制剂的发展和临床应用存在诸多挑战，而这些抑制剂目前是针对细胞内蛋白的主要靶向治疗类型。PROteolysis-TArgeting Chimeras（PROTACs）利用细胞内的泛素-蛋白酶体系统来选择性地降解靶蛋白。最近，高活性的小分子 PROTACs 经常被报道。在这篇综述中，我们总结了小分子 PROTACs 的新兴特征，如诱导快速、深刻和持续的降解，诱导下游信号的强大抑制，显示出增强的靶标选择性，并克服对小分子抑制剂的耐药性。在肿瘤异种移植模型中，小分子 PROTACs 可显著抑制肿瘤进展。此外，我们还介绍了 PROTAC 技术的最新进展，如同型 PROTACs。与传统小分子药物相比，小分子 PROTAC 技术具有突出的优势，且有很有前景的临床前数据表明，小分子 PROTAC 技术有可能极大地促进靶向治疗药物的发展。
