Procaspase-3 Activation

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.

Diagram showing how 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.
Diagram of PAC-1 on left and S-PAC-1 on right.

Related Publications:

  1. The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma
    Boudreau MW, Tonogai EJ, Schane CP, Xi MX, Fischer JH, Vijayakumar J, Ji Y, Tarasow TM, Fan TM, Hergenrother PJ, Dudek AZ
    Melanoma Res. 2023, 33, 514-524

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  1. Phase 1 dose escalation study of procaspase activating compound-1 (PAC-1) in combination with temozolomide in patients with recurrent high-grade astrocytomas
    Holdhoff M, Nicholas KM, Peterson RA, Maraka S, Liu LC, Fischer JH, Wefel JS, Fan TM, Vannorsdall T, Russell M, Iacoboni M, Tarasow TM, Hergenrother PJ, Dudek AZ, Danciu OC
    Neuro-Oncol. Adv. 2023, 5, vdad087

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  1. Phase 1 study of procaspase activating compound-1 (PAC-1) in the treatment of advanced malignancies
    Danciu OC, Holdhoff M, Peterson RA, Fisher JH, Liu LC, Wang H, Venepalli NK, Chowdhery R, Nicholas MK, Russell MJ, Fan TM, Hergenrother PJ, Tarasow TM, Dudek AZ
    Brit. J. Cancer 2023, 128, 783

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  1. Evaluation of a procaspase-3 activator with hydroxyureas or temozolomide against high-grade meningioma in cell culture and canine cancer patients
    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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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PARG Inhibition
Activation by NQO1
ErSO-related Compounds
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