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Protein degradation

Prime time for PROTACs

Nature Chemical Biology volume 11, pages 634–635 (2015)Cite this article

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A Corrigendum to this article was published on 20 October 2015

This article has been updated

PROTACs are heterobifunctional small molecules that simultaneously bind a target protein and a ubiquitin ligase, enabling ubiquitination and degradation of the target. Major progress in developing potent and specific PROTACs has recently been reported, invigorating prospects for novel PROTAC-based therapies.

The major stumbling block to effective and widespread implementation of the PROTAC approach over the past decade has been the lack of a small molecule that binds to a ubiquitin ligase with good affinity and specificity and has a known binding pose. The original PROTACs1 used peptides derived from natural ubiquitin ligase substrates, but these suffered from multiple limitations, including large size, poor cellular uptake and metabolism. Remarkably, after years of steady advances, there has been a spectacular leap in performance, and now there are two low–molecular weight (low-MW), exquisitely specific, high-affinity E3 ligands that enable the assembly of potent PROTACs.

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Figure 1: PROTAC mechanism of action and modular structure.

Katie Vicari/Nature Publishing Group

Change history

  • 23 September 2015

    In the version of this article originally published, the protein ERRα was mislabeled as BRD4 in Figure 1 and its legend, and the citation of the figure in the text was misplaced. These errors have been corrected in the HTML and PDF versions of the article.

References

  1. Sakamoto, K.M. et al. Proc. Natl. Acad. Sci. USA 98, 8554–8559 (2001).

    Article  CAS  Google Scholar 

  2. Buckley, D.L. & Crews, C.M. Angew. Chem. Int. Edn. Engl. 53, 2312–2330 (2014).

    Article  CAS  Google Scholar 

  3. Buckley, D.L. et al. ACS Chem. Biol. doi:10.1021/acschembio.5b00442 (2015).

  4. Lu, J. et al. Chem. Biol. 22, 755–763 (2015).

    Article  CAS  Google Scholar 

  5. Winter, G.E. et al. Science 348, 1376–1381 (2015).

    Article  CAS  Google Scholar 

  6. Zengerle, M., Chan, K.H. & Ciulli, A. ACS Chem. Biol. doi:10.1021/acschembio.5b00216 (2015).

  7. Bondeson, D.P. et al. Nat. Chem. Biol. 11, 611–617 (2015).

    Article  CAS  Google Scholar 

  8. Ito, T.H. et al. Science 327, 1345–1350 (2010).

    Article  CAS  Google Scholar 

  9. Krönke, J. et al. Science 343, 301–305 (2014).

    Article  Google Scholar 

  10. Lu, G. et al. Science 343, 305–309 (2014).

    Article  CAS  Google Scholar 

  11. Gandhi, A.K. et al. Br. J. Haematol. 164, 811–821 (2014).

    Article  CAS  Google Scholar 

  12. Fischer, E.S. et al. Nature 512, 49–53 (2014).

    Article  CAS  Google Scholar 

  13. Chamberlain, P.P. et al. Nat. Struct. Mol. Biol. 21, 803–809 (2014).

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Raymond J. Deshaies is in the Howard Hughes Medical Institute and Division of Biology and Biological Engineering, Caltech, Pasadena, California, USA.,

    Raymond J Deshaies

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  1. Raymond J Deshaies
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Correspondence to Raymond J Deshaies.

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Competing interests

R.J.D. is co-founder of a company (Cleave Biosciences) that is developing therapeutics based on targeting enzymes in the ubiquitin-proteasome pathway. R.J.D. also holds stock in Cleave Biosciences and serves as a consultant and member of their Scientific Advisory Board.

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Deshaies, R. Prime time for PROTACs. Nat Chem Biol 11, 634–635 (2015). https://doi.org/10.1038/nchembio.1887

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