The broad, long-term objective of the work proposed herein is to validate a novel strategy for anti-cancer therapy. A hallmark of cancerous cells is their ability to resist apoptosis and become immortal. This resistance is typically due to mutations in or aberrant expression of a wide variety of proteins in the apoptotic cascade. These alterations are effectively """"""""breaks"""""""" in the apoptotic circuitry, which prevent proapoptotic signals from being transmitted to activate procaspase-3 to caspase-3. Caspase-3 is the major """"""""executioner"""""""" caspase that is responsible for the proteolysis of hundreds of cellular substrates. Interestingly, procaspase-3 levels are elevated in a variety of cancers, but the defective apoptotic machinery simply cannot activate this zymogen. Described herein is an anti-cancer strategy to directly activate, with a small molecule, procaspase-3 to active caspase-3. In exciting preliminary results we have, through high-throughput screening, identified a procaspase-3 activating compound that we call PAC-1. In cell culture, PAC-1 induces apoptotic cell death, and its potency is directly proportional to the amount of procaspase-3 present in the cell. PAC-1 also powerfully induced apoptotic death in cells from primary colon tumors, with a potency strictly dependent on the amount of procaspase-3 in the cells. We have shown PAC-1 to be active in three different mouse models of cancer. In the proposed work we will use this discovery of PAC-1 as a springboard to probe the apoptotic pathways, evaluate the pharmacokinetics, efficacy, and toxicity of PAC-1 and derivatives in mice, and elucidate the biochemical mechanism by which PAC-1 activates procaspase-3. Public health relevance. Cancer has now overtaken heart disease as the leading cause of death in the U.S and is an enormous public health problem. Mutations in the fundamental cell death machinery enable cancerous cells to resist natural defenses and chemotherapeutic treatments. We propose a strategy by which we will completely bypass the mutated circuitry and activate the death pathway in cancer cells, thus killing the cancer and saving the life of the patient.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120439-04
Application #
7845724
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2007-08-06
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$221,535
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Joshi, Avadhut D; Botham, Rachel C; Schlein, Lisa J et al. (2017) 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. Oncotarget 8:80124-80138
Peh, Jessie; Fan, Timothy M; Wycislo, Kathryn L et al. (2016) The Combination of Vemurafenib and Procaspase-3 Activation Is Synergistic in Mutant BRAF Melanomas. Mol Cancer Ther 15:1859-69
Botham, Rachel C; Roth, Howard S; Book, Alison P et al. (2016) Small-Molecule Procaspase-3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics. ACS Cent Sci 2:545-59
Roth, Howard S; Hergenrother, Paul J (2016) Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities. Curr Med Chem 23:201-41
Palchaudhuri, Rahul; Lambrecht, Michael J; Botham, Rachel C et al. (2015) A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed. Cell Rep 13:2027-36
Roth, Howard S; Botham, Rachel C; Schmid, Steven C et al. (2015) Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics. J Med Chem 58:4046-65
Botham, Rachel C; Fan, Timothy M; Im, Isak et al. (2014) Dual small-molecule targeting of procaspase-3 dramatically enhances zymogen activation and anticancer activity. J Am Chem Soc 136:1312-9
Hsu, Danny C; Roth, Howard S; West, Diana C et al. (2012) Parallel synthesis and biological evaluation of 837 analogues of procaspase-activating compound 1 (PAC-1). ACS Comb Sci 14:44-50
West, Diana C; Qin, Yan; Peterson, Quinn P et al. (2012) Differential effects of procaspase-3 activating compounds in the induction of cancer cell death. Mol Pharm 9:1425-34
Palchaudhuri, Rahul; Hergenrother, Paul J (2011) Transcript profiling and RNA interference as tools to identify small molecule mechanisms and therapeutic potential. ACS Chem Biol 6:21-33

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