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The development of novel drug modalities is necessary to overcome the current critical issues in the treatment of cancer, namely toxicity, insufficient efficacy, and the development of resistance. Unlike classical small molecule inhibitors that only block a single function or interaction of a protein involved in oncogenic signaling, proteolysis-targeting chimeras (PROTACs) degrade the entire protein, thus offering a potential paradigm shift. PROTACs are bivalent small molecules that recruit a target protein in proximity to an E3 ligase, promoting the transfer of ubiquitin, which marks the protein for proteasomal degradation. Because of their unique properties, PROTACs offer an attractive alternative as targeted therapeutics. The first PROTAC entered the clinic 5 years ago, and since then more than 30 have followed. In this review, we discuss the current compounds being investigated in the clinic, the key aspects of their design, and their potential for treating cancer.
Vetma et al. (Wed,) studied this question.