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Science 326 (5954): 853-858

Copyright © 2009 by the American Association for the Advancement of Science

Small-Molecule Activators of a Proenzyme

Dennis W. Wolan, Julie A. Zorn, Daniel C. Gray, James A. Wells*

Abstract: Virtually all of the 560 human proteases are stored as inactive proenyzmes and are strictly regulated. We report the identification and characterization of the first small molecules that directly activate proenzymes, the apoptotic procaspases-3 and -6. It is surprising that these compounds induce autoproteolytic activation by stabilizing a conformation that is both more active and more susceptible to intermolecular proteolysis. These procaspase activators bypass the normal upstream proapoptotic signaling cascades and induce rapid apoptosis in a variety of cell lines. Systematic biochemical and biophysical analyses identified a cluster of mutations in procaspase-3 that resist small-molecule activation both in vitro and in cells. Compounds that induce gain of function are rare, and the activators reported here will enable direct control of the executioner caspases in apoptosis and in cellular differentiation. More generally, these studies presage the discovery of other proenzyme activators to explore fundamental processes of proenzyme activation and their fate-determining roles in biology.

Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, Byers Hall, 1700 4th Street, San Francisco, CA 94158, USA.

*To whom correspondence should be addressed. E-mail: jim.wells{at}

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Autoactivation of Thrombin Precursors.
N. Pozzi, Z. Chen, F. Zapata, W. Niu, S. Barranco-Medina, L. A. Pelc, and E. Di Cera (2013)
J. Biol. Chem. 288, 11601-11610
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Systems Analysis of Cancer Cell Heterogeneity in Caspase-dependent Apoptosis Subsequent to Mitochondrial Outer Membrane Permeabilization.
J. Schmid, H. Dussmann, G. J. Boukes, L. Flanagan, A. U. Lindner, C. L. O'Connor, M. Rehm, J. H. M. Prehn, and H. J. Huber (2012)
J. Biol. Chem. 287, 41546-41559
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Fibrils Colocalize Caspase-3 with Procaspase-3 to Foster Maturation.
J. A. Zorn, D. W. Wolan, N. J. Agard, and J. A. Wells (2012)
J. Biol. Chem. 287, 33781-33795
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Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy.
S. Hector, M. Rehm, J. Schmid, J. Kehoe, N. McCawley, P. Dicker, F. Murray, D. McNamara, E. W. Kay, C. G. Concannon, et al. (2012)
Gut 61, 725-733
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Structural and Enzymatic Insights into Caspase-2 Protein Substrate Recognition and Catalysis.
Y. Tang, J. A. Wells, and M. R. Arkin (2011)
J. Biol. Chem. 286, 34147-34154
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Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways.
T.-F. Chou, S. J. Brown, D. Minond, B. E. Nordin, K. Li, A. C. Jones, P. Chase, P. R. Porubsky, B. M. Stoltz, F. J. Schoenen, et al. (2011)
PNAS 108, 4834-4839
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Allosteric Peptide Activators of Pro-Hepatocyte Growth Factor Stimulate Met Signaling.
K. E. Landgraf, L. Santell, K. L. Billeci, C. Quan, J. C. Young, H. R. Maun, D. Kirchhofer, and R. A. Lazarus (2010)
J. Biol. Chem. 285, 40362-40372
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Crystal structures of human caspase 6 reveal a new mechanism for intramolecular cleavage self-activation.
X.-J. Wang, Q. Cao, X. Liu, K.-T. Wang, W. Mi, Y. Zhang, L.-F. Li, A. C. LeBlanc, and X.-D. Su (2010)
EMBO Rep. 11, 841-847
   Abstract »    Full Text »    PDF »

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