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Targeted protein degradation: expanding the toolbox

Nature Reviews Drug Discovery volume 18, pages 949–963 (2019)Cite this article

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Abstract

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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Fig. 1: Substrate recruitment in targeted protein degradation.
Fig. 2: Structures of ternary complexes formed during targeted protein degradation.
Fig. 3: Tissue expression of E3 ligases.
Fig. 4: Ligandability of E3 ligases: DCAF and BTB E3 ligases.
Fig. 5: Ligandability of E3 ligases: BC-box, F-box, IAP and APC E3 ligases.
Fig. 6: Ligandability of E3 ligases: HECT and TRIM E3 ligases.

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Acknowledgements

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.

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Authors and Affiliations

  1. Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

    Matthieu Schapira

  2. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

    Matthieu Schapira

  3. Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA

    Matthew F. Calabrese

  4. Structural Genomics Consortium, University of Oxford, Oxford, UK

    Alex N. Bullock

  5. Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA

    Craig M. Crews

  6. Department of Chemistry, Yale University, New Haven, CT, USA

    Craig M. Crews

  7. Department of Pharmacology, Yale University, New Haven, CT, USA

    Craig M. Crews

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Correspondence to Matthieu Schapira.

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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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Arvinas press release: http://ir.arvinas.com/news-releases/news-release-details/arvinas-present-preclinical-tau-directed-protacr-protein

The Human Protein Atlas: https://www.proteinatlas.org/

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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

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