Abstract- 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 systemto 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.
