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PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics

Abstract

Using PROteolysis TArgeting Chimeras (PROTACs) to degrade proteins that are important for tumorigenesis has emerged as a potential therapeutic strategy for cancer. PROTACs are heterobifunctional molecules consisting of one ligand for binding to a protein of interest (POI) and another to an E3 ubiquitin (E3) ligase, connected via a linker. PROTACs recruit the E3 ligase to the POI and cause proximity-induced ubiquitination and degradation of the POI by the ubiquitin-proteasome system (UPS). PROTACs have been developed to degrade a variety of cancer targets with unprecedented efficacy against a multitude of tumor types. To date, most of the PROTACs developed have utilized ligands to recruit E3 ligases that are ubiquitously expressed in both tumor and normal tissues. These PROTACs can cause on-target toxicities if the POIs are not tumor-specific. Therefore, identifying and recruiting the E3 ligases that are enriched in tumors with minimal expression in normal tissues holds the potential to develop tumor-specific/selective PROTACs. In this review, we will discuss the potential of PROTACs to become anticancer therapeutics, chemical and bioinformatics approaches for PROTAC design, and safety concerns with a special focus on the development of tumor-specific/selective PROTACs. In addition, the identification of tumor types in terms of solid versus hematological malignancies that can be best targeted with PROTAC approach will be briefly discussed.

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Fig. 1: Mechanisms of PROTAC-mediated protein degradation.
Fig. 2: Milestones in PROTAC discovery.
Fig. 3: Profile of E3 ligase expression in normal tissues.
Fig. 4: Distribution of E3 ligases in normal tissues.
Fig. 5: Identification of tumor-specific/selective E3 ligases.

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Acknowledgements

The authors would like to thank the members of the Zheng and Zhou laboratories for thoughtful discussion and assistance. We greatly acknowledge help from Ms. Janet S. Wiegand for grammatical corrections. This study was supported by US National Institutes of Health (NIH) grants R01CA211963 (DZ), R01CA219836 (DZ), R01CA242003 (DZ and GZ) and R21CA223371 (GZ).

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Correspondence to Daohong Zhou.

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SK, YH, XZ, GZ, and DZ are inventors of two pending patent applications for use of Bcl-xL PROTACs as senolytic and antitumor agents. GZ, and DZ are co-founders of and have equity in Dialectic Therapeutics, which develops Bcl-xL PROTACs to treat cancer. The remaining authors declare no conflict of interests.

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Khan, S., He, Y., Zhang, X. et al. PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics. Oncogene 39, 4909–4924 (2020). https://doi.org/10.1038/s41388-020-1336-y

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