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.

  • Correspondence
  • Published:

Small molecules not direct activators of caspases

Nature Chemical Biology volume 3, page 519 (2007)Cite this article

A Correspondence to this article was published on 01 September 2007

Access through your institution
Buy or subscribe

To the editor

Apoptosis is executed by the effector caspases-3 and -7, which normally reside as latent precursors (zymogens) in most of the nucleated cells of the human body. The physiologic mechanism for their activation requires cleavage, and such cleavage is generated by a proteolytic attack by the apical caspase-8 or caspase-9, or by the caspase analog granzyme B. It therefore came as an exciting surprise when, in a previous issue of Nature Chemical Biology1, Hergenrother and colleagues reported on a series of small molecules that could directly activate the zymogens of caspases-3 and -7, because such compounds could form the basis of new anti-neoplastic therapeutics. In the normal process, proteolysis of caspase zymogens results in a gain of activity of several orders of magnitude2. Hence, we were surprised that Putt and co-workers could only obtain a 3–4.5-fold relative increase in activity (as monitored by UV), especially since the authors observed >50% cleavage of procaspase-3 within 4 h by western blotting; this apparent discrepancy prompted us to examine the utility of PAC-1.

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

Relevant articles

Open Access articles citing this article.

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Lack of activation or processing of procaspase-3 by PACs.

References

  1. Putt, K.S. et al. Nat. Chem. Biol. 2, 543–550 (2006).

    Article  PubMed  Google Scholar 

  2. Zhou, Q. & Salvesen, G.S. Biochem. J. 324, 361–364 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Li, P. et al. Cell 91, 479–489 (1997).

    Article  PubMed  Google Scholar 

  4. Ellerby, H.M. et al. J. Neurosci. 17, 6165–6178 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stennicke, H.R. & Salvesen, G.S. Methods 17, 313–319 (1999).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, 92037, California, USA

    Jean-Bernard Denault, Marcin Drag & Guy S Salvesen

  2. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Dr., San Diego, 92121, California, USA

    Juliano Alves, Analeah B Heidt, Quinn Deveraux & Jennifer L Harris

Authors
  1. Jean-Bernard Denault
    View author publications

    Search author on:PubMed Google Scholar

  2. Marcin Drag
    View author publications

    Search author on:PubMed Google Scholar

  3. Guy S Salvesen
    View author publications

    Search author on:PubMed Google Scholar

  4. Juliano Alves
    View author publications

    Search author on:PubMed Google Scholar

  5. Analeah B Heidt
    View author publications

    Search author on:PubMed Google Scholar

  6. Quinn Deveraux
    View author publications

    Search author on:PubMed Google Scholar

  7. Jennifer L Harris
    View author publications

    Search author on:PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Denault, JB., Drag, M., Salvesen, G. et al. Small molecules not direct activators of caspases. Nat Chem Biol 3, 519 (2007). https://doi.org/10.1038/nchembio0907-519

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio0907-519

This article is cited by

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