Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

• Main Authors: Sainan An, Liwu Fu
• Format: Article
• Language: English
• Published: Elsevier 2018-10-01
• Series: EBioMedicine
• Online Access: http://www.sciencedirect.com/science/article/pii/S2352396418303621

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. Keywords: PROTAC, Induced protein degradation, E3 ligases, Ubiquitin-proteasome system, Targeted therapy drugs