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.
Related Publications:
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Tonogai, E.; Huang, S.; Botham, R.; Berry, M.; Joslyn, S.; Daniel, G.; Chen, Z.; Rao, J.; Zhang, X.; Basuli, F.; Rossmisl, J.; Riggins, G.; LeBlanc, A.; Fan, T.; Hergenrother, P.J.
Neuro-Oncology 2021, 23, 1723-1735.
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- Procaspase-3 Overexpression in Cancer: A Paradoxical Observation with Therapeutic Potential
Boudreau, M. W.; Peh, J.; Hergenrother, P. J.
ACS Chem. Biol. 2019, 14, 2335-2348.
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- Immunohistochemical characterization of procaspase-3 overexpression as a druggable target with PAC-1, a procaspase-3 activator, in canine and human brain cancers
Schlein, L. J.; Fadl-Alla, B.; Pondenis, H. C.; Lezmi, S.; Eberhart, C. G.; LeBlanc, A. K.; Dickinson, P. J.; Hergenrother, P. J.; Fan, T. M.
Front. Oncol. 2019, 9, 96
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- Overcoming resistance to targeted anticancer therapies through small-molecule mediated MEK degradation
Peh, J.; Boudreau, M. W.; Smith, H. M.; and Hergenrother, P. J.
Cell Chem. Biol. 2018, 25, 996-1005.
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- Synergistic and targeted therapy with a procaspase-3 activator and temozolomide extends survival in glioma rodent models and is feasible for the treatment of canine malignant glioma patients
Joshi, A. D.; Botham, R. C.; Schlein, L. J.; Roth, H. S.; Mangraviti, A.; Borodovsky, A.; Tyler, B.; Joslyn, S.; Looper, J. S.; Podell, M.; Fan, T. F.; Hergenrother, P. J.;
Riggins, G. J.
Oncotarget 2017, 8, 80124-80138.
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- Small-Molecule Procaspase-3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics
Botham, R. C.; Roth, H. S.; Book, A. P.; Roady, P. J.; Fan, T. M.; Hergenrother, P. J.
ACS Central Science 2016, 2, 545-559.
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- The Combination of Vemurafenib and Procaspase-3 Activation is Synergistic in Mutant BRAF Melanomas
Peh, J.; Fan, T. M.; Wycislo, K. L.; Roth, H. S.; Hergenrother, P. J.
Mol. Cancer Ther. 2016, 15, 1859-1869.
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- Derivatives of Procaspase-Activating Compound 1 (PAC-1) and Their Anticancer Activities
Roth, H. S.; Hergenrother, P. J.
Curr. Med. Chem. 2016, 23, 201-241 (review).
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- Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics
Roth, H. S.; Botham, R. C.; Schmid, S. C.; Fan, T. M.; Dirikolu, L.; Hergenrother, P. J.
J. Med. Chem. 2015, 58, 4046-4065.
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- Dual Small-Molecule Targeting of Procaspase-3 Dramatically Enhances Zymogen Activation and Anticancer Activity
Botham, R. C.; Fan, T. M.; Im, I.; Borst, L. B.; Dirikolu, L.; Hergenrother, P. J.
J. Am. Chem. Soc. 2014, 136, 1312-1319.
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- Differential effects of procaspase-3 activating compounds in the induction of cancer cell death
West, D. C.; Qin, Y.; Peterson, Q. P.; Thomas, D. L.; Palchaudhuri, R. P.; Morrison, K. C.; Lucas, P. W.; Palmer, A. E.; Fan, T. M; Hergenrother, P. J.
Mol. Pharmaceutics 2012, 9, 1425-1434.
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- Parallel Synthesis and Biological Evaluation of 837 Analogues of Procaspase-Activating Compound 1 (PAC-1)
Hsu, D. C.; Roth, H. S.; West, D. C.; Botham, R. C.; Novotny, C. J.; Schmid, S. C.; Hergenrother, P. J.
ACS Comb. Sci. 2012, 14, 44-50.
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- Pharmacokinetics and Derivation of an Anticancer Dosing Regimen for PAC-1, a Preferential Small Molecule Activator of Procaspase-3, in Healthy Dogs
Lucas, P. W.; Schmit, J. M.; Peterson, Q. P.; West, D. C.; Hsu, D. C.; Novotny, C. J.; Dirikoul, L.; Deorge, D. R.; Garrett, L. D.; Hergenrother, P. J.; Fan, T. M.
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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- Preparation of the Caspase-3/-7 Substrate Ac-DEVD-pNA via Solution-Phase Peptide Synthesis
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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- Small-Molecule Activation of Procaspase-3 to Caspase-3 as a Personalized Anticancer Strategy
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.
Nat. Chem. Biol. 2006, 2, 543-50.
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