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Targeted protein degraders: a call for collective action to advance safety assessment

Targeted protein degraders (TPDs) are emerging classes of therapeutics that have the potential to address difficult drug targets in new ways. In 2021, experts convened to discuss challenges in TPD safety evaluation, and supported supplementing individual efforts to address these challenges with collective development of novel decision frameworks, tools and a shared evidence base.
  1. Lyn H. Jones

    1. Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, MA, USA.

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  2. Constance A. Mitchell

    1. Health and Environmental Sciences Institute, Washington, DC, USA.

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  3. Lise Loberg

    1. AbbVie, North Chicago, IL, USA.

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  4. Mira Pavkovic

    1. Bayer, Wuppertal, Germany.

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  5. Mohan Rao

    1. Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.

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  6. Ruth Roberts

    1. ApconiX, Alderley Edge, UK; Department of Biosciences, University of Birmingham, Birmingham, UK.

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  7. Katie Stamp

    1. Bristol Myers Squibb, New York, NY, USA.

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  8. Laurie Volak

    1. Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.

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  9. Matthias B. Wittwer

    1. Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.

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  10. Syril Pettit

    1. Health and Environmental Sciences Institute, Washington, DC, USA.

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Targeted protein degraders (TPDs) — including molecular glues and heterobifunctional molecules — are rapidly evolving classes of drugs that are being investigated to treat cancer and other diseases1. They are characterized by use of endogenous protein degradation processes to target previously ‘undruggable’ proteins, as well as established drug targets in new ways.

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Nature Reviews Drug Discovery 21, 401-402 (2022)

doi: https://doi.org/10.1038/d41573-022-00055-9

Acknowledgements

This work was supported by the Health and Environmental Science Institute (HESI). The authors gratefully acknowledge the contributions of all speakers and the input from workshop participants of all sectors and geographical areas for enriching the discussions.

References

  1. Chamberlain, P. P. & Hamann, L.G. Development of targeted protein degradation therapeutics. Nat. Chem. Biol. 15, 937–944 (2019).

    Article  PubMed  Google Scholar 

  2. Bekes, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. 21, 181–200 (2022).

    Article  PubMed  Google Scholar 

  3. Moreau, K. et al. Proteolysis-targeting chimeras in drug development: a safety perspective. Br. J. Pharmacol. 177, 1709–1718 (2020).

    Article  PubMed  Google Scholar 

  4. Donovan, K. A. et al. Mapping the degradable kinome provides a resource for expedited degrader development. Cell 183, 1714–1731.e10 (2020).

    Article  PubMed  Google Scholar 

  5. Nowak, R. & Jones, L, H. Target validation using PROTACs: applying the four pillars framework. SLAS Discov. 26, 474–483 (2021).

    Article  PubMed  Google Scholar 

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Supplementary Information

  1. Supplementary information

Competing Interests

HESI does not have a direct conflict of interest and holds no financial stake in specific pharmaceutical products or methods. The HESI scientific programming described in this article was supported by in-kind contributions from public and private sector participants of time, expertise and experimental effort, and direct funding from multiple pharmaceutical companies. A list of supporting organizations is available at www.hesiglobal.org. L.H.J. serves on the scientific advisory board for, and holds equity in, Interline Therapeutics, Umbra Therapeutics and Rapafusyn Pharmaceuticals. He also holds equity in Jnana Therapeutics and consults for EoCys. The Center for Protein Degradation at DFCI receives research funding from Deerfield. L.L., M.P., M.R, R.R., K.S., L.V. and M.B.W. are employed by companies engaged in the TPD field as indicated in their affiliations.

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