Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Targeted protein degradation

CIDE-stepping E3s

Nature Chemical Biology volume 19, pages 3–4 (2023)Cite this article

Subjects

Small-molecule-mediated targeted protein degradation (TPD) relies on the recruitment of a target protein of interest to an E3 ligase. A new study indicates how direct target recruitment to the 26S proteasome can bypass this requirement.

Of the 600 known E3 ligases, approximately 1% have been identified as tractable for TPD. CRL4CRBN and CRL2VHL are the most frequently used, and PROTACs leveraging each of these ligases have entered human clinical investigation3. Thalidomide and its analogs (collectively often referred to as ‘IMiDs’) are a class of CRBN-binding MGDs that are clinically approved4. Despite clinical success, however, the emergence of resistance to IMiDs poses a challenge. Remarkably, around one-third of patients who relapse after IMiD treatment feature alterations in CRBN5. This indicates that E3s could, in general, be an Achilles’ heel for TPD-based therapies. Hence, alternative strategies to induced protein ablation are needed.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Conceptual depiction of targeted protein degradation.

References

  1. Hanzl, A. et al. Curr. Opin. Chem. Biol. 56, 35–41 (2020).

    Article  CAS  Google Scholar 

  2. Bashore, C. et al. Nat. Chem. Biol. https://doi.org/10.1038/s41589-022-01218-w (2022).

  3. Békés, M. et al. Nat. Rev. Drug Discov. 21, 181–200 (2022).

    Article  Google Scholar 

  4. Jan, M. et al. Nat. Rev. Clin. Oncol. 18, 401–417 (2021).

    Article  Google Scholar 

  5. Gooding, S. et al. Blood. 137, 232–237 (2021).

    Article  CAS  Google Scholar 

  6. Murakami, Y. et al. Nature. 360, 597–599 (1992).

    Article  CAS  Google Scholar 

  7. Finley, D. et al. Cold Spring Harb. Perspect. Biol. 12, a033985 (2020).

    Article  CAS  Google Scholar 

  8. Schneider, M. et al. Nat. Rev. Drug Discov. 20, 789–797 (2021).

    Article  CAS  Google Scholar 

  9. Ng, C. et al. Curr. Opin. Chem. Biol. 67, 102107 (2022).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Gary Tin & Georg E. Winter

Authors
  1. Gary Tin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Georg E. Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Georg E. Winter.

Ethics declarations

Competing interests

G.E.W. is scientific founder and shareholder of Proxygen and Solgate. The Winter lab receives research funding from Pfizer.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tin, G., Winter, G.E. CIDE-stepping E3s. Nat Chem Biol 19, 3–4 (2023). https://doi.org/10.1038/s41589-022-01217-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-022-01217-x

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing