Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin–proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating ‘undruggable’ targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.
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The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute (OGI-055, Innovative Medicines Initiative (EU/EFPIA, ULTRA-DD grant no. 115766), Janssen, Merck KGaA, Darmstadt, Germany, MSD, Novartis Pharma AG, Innovation and Science (MRIS), Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome (grant 106169/ZZ14/Z). M.S. gratefully acknowledges support from NSERC (grant RGPIN-2019-04416). Research in the C.M.C. lab is supported by grant NIH R35CA197589 and by Arvinas.
M.F.C. is an employee of Pfizer. C.M.C. is a consultant and shareholder in Arvinas, which provides research support to his lab.
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Schapira, M., Calabrese, M.F., Bullock, A.N. et al. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov 18, 949–963 (2019). https://doi.org/10.1038/s41573-019-0047-y