Cellular apoptotic pathways converge on the activation of procaspase-3, resulting in the production of active caspase-3. Caspase-3 catalyzes the hydrolysis of hundreds of cellular substrates and, once activated, rapidly induces apoptotic cell death. In 2006 we reported PAC-1 as the first small molecule to directly activate procaspase-3, and since then we have defined the mechanism by which this compound activates procaspase-3, and have synthesized hundreds of derivatives. Given that procaspase-3 levels are elevated in many tumor tissues, PAC-1 and related compounds have considerable potential for treatment of cancer. Toward this end, PAC-1 and its derivative S-PAC-1 have been evaluated in canine cancer patients, and PAC-1 is now being administered to human cancer patients through a Phase I clinical trial at the University of Illinois Cancer Center in Chicago and at Johns Hopkins University. See more information at clinicaltrials.gov.


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ACS Comb. Sci. 2012, 14, 44-50.
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Invest. New Drugs 2011, 29, 901-911.
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- Discovery and Canine Preclinical Assessment of a Nontoxic Procaspase-3-Activating Compound
Peterson, Q. P.; Hsu, D. C.; Novotny, C. J.; West, D. C.; Kim, D.; Schmit, J. M.; Dirikolu, L.; Hergenrother, P. J.; Fan, T. M.
Cancer Res. 2010, 70, 7232-7241.
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Peterson, Q. P.; Goode, D. R.; West, D. C.; Botham, R. C.; Hergenrother, P. J.
Nature Protocols 2010, 5, 294-302.
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- Procaspase-3 Activation as an Anti-Cancer Strategy: Structure-Activity Relationship of PAC-1, and its Cellular Co-Localization with Caspase-3
Peterson, Q. P.; Hsu, D. C.; Goode, D. R.; Novotny, C. J.; Totten, R. K.; Hergenrother, P. J.
J. Med. Chem. 2009, 52, 5721-5731.
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- PAC-1 Activates Procaspase-3 in vitro Through Relief of Zinc-Mediated Inhibition
Peterson, Q. P.; Goode, D. R.; West, D. C.; Ramsey, K. N.; Lee, J. J.; Hergenrother, P. J.
J. Mol. Biol. 2009, 388, 144-158.
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Putt, K. S.; Chen, G. W.; Pearson, J. M.; Sandhorst, J. S.; Hoagland, M. S.; Kwon, J.-T.; Hwang, S.-K.; Jin, H.; Churchwell, M. I.; Cho, M.-H.; Doerge, D. R.; Helferich, W. G.; Hergenrother, P. J.
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