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The PROTACtable genome

Nature Reviews Drug Discovery volume 20, pages 789–797 (2021)Cite this article

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Abstract

Proteolysis-targeting chimeras (PROTACs) are an emerging drug modality that may offer new opportunities to circumvent some of the limitations associated with traditional small-molecule therapeutics. By analogy with the concept of the ‘druggable genome’, the question arises as to which potential drug targets might PROTAC-mediated protein degradation be most applicable. Here, we present a systematic approach to the assessment of the PROTAC tractability (PROTACtability) of protein targets using a series of criteria based on data and information from a diverse range of relevant publicly available resources. Our approach could support decision-making on whether or not a particular target may be amenable to modulation using a PROTAC. Using our approach, we identified 1,067 proteins of the human proteome that have not yet been described in the literature as PROTAC targets that offer potential opportunities for future PROTAC-based efforts.

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Fig. 1: Targeted protein degradation by PROTACs.
Fig. 2: Overview of the data sources and assignment rules for the workflow to assess target PROTACtability.
Fig. 3: Exploring the PROTACtable genome.
Fig. 4: Comparison of the PROTACtable genome with the druggable genome.

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Data availability

The full output of the PROTACtability assessment pipeline is provided as an Excel spreadsheet (Supplementary Table 1); each row corresponds to a protein-coding gene and the columns represent the various bucket assessment results or data types. A more detailed description of the column headings can be found in Supplementary Box 1 and in the main text.

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Acknowledgements

The authors thank A. Ciulli, E. Fischer and M. Calabrese for their constructive feedback on our original manuscript. This work was funded by the Open Targets consortium and the Member States of the European Molecular Biology Laboratory (EMBL).

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Author notes

  1. Chris J. Radoux

    Present address: Exscientia, Oxford, UK

  2. Kris Brown

    Present address: Agenus, Lexington, MA, USA

Authors and Affiliations

  1. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK

    Melanie Schneider, Chris J. Radoux, Andrew Hercules, David Ochoa, Ian Dunham & Andrew R. Leach

  2. Open Targets, Wellcome Genome Campus, Hinxton, UK

    Melanie Schneider, Chris J. Radoux, Andrew Hercules, David Ochoa, Ian Dunham, Lykourgos-Panagiotis Zalmas & Andrew R. Leach

  3. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK

    Lykourgos-Panagiotis Zalmas

  4. Integrated Drug Discovery, Sanofi-Aventis Deutschland, Frankfurt am Main, Germany

    Gerhard Hessler & Sven Ruf

  5. Bristol Myers Squibb, Cambridge, MA, USA

    Veerabahu Shanmugasundaram

  6. GlaxoSmithKline, GSK Medicines Research Centre, Stevenage, UK

    Michael M. Hann, Pam J. Thomas, Markus A. Queisser & Andrew B. Benowitz

  7. GlaxoSmithKline, Collegeville, PA, USA

    Kris Brown

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Correspondence to Andrew R. Leach.

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Competing interests

G.H., S.R., V.S., M.M.H., P.J.T., M.A.Q., A.B.B. and K.B. work for companies involved in the discovery of PROTAC compounds as part of their overall drug discovery efforts. The other authors declare no competing interests.

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Nature Reviews Drug Discovery thanks A. Ciulli, E. Fischer and M. Calabrese for their contribution to the peer review of this work.

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Related Links

Open Targets Platform: https://platform.opentargets.org/

Open Targets scoring scheme: https://platform-docs.opentargets.org/associations

Pharos API: https://pharos.nih.gov/api

PROTACpedia: http://protacdb.weizmann.ac.il/ptcb/main

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Schneider, M., Radoux, C.J., Hercules, A. et al. The PROTACtable genome. Nat Rev Drug Discov 20, 789–797 (2021). https://doi.org/10.1038/s41573-021-00245-x

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