Small‐Molecule Procaspase Activators Identified Using Fluorescence Polarization

Vickers, Chris J.; González-Páez, Gonzalo E.; Umotoy, Jeffrey C.; Cayanan-Garrett, Charmagne; Brown, Steven J; Wolan, Dennis W.

doi:10.1002/cbic.201300315

Cited by 16 publications

(19 citation statements)

References 31 publications

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“…7 Similarly, small molecules capable of enhancing the activity of proapoptotic proteins hold promise for the treatment of cancer. One target that has received considerable attention is procaspase-3, 8–11 a member of the caspase family of proteases critical to apoptosis. Both the intrinsic and extrinsic pathways of apoptosis converge to activate executioner caspases-3, -6, and -7, from their proenzyme forms.…”

Section: Introductionmentioning

confidence: 99%

“…12, 13 The low frequency of procaspase-3 mutations in cancer, 14 its downstream location relative to apoptotic proteins that are frequently mutated, 13 and the overexpression of procaspase-3 in a number of cancer types, including lymphoma, 15, 16 leukemia, 17, 18 melanoma, 19, 20 glioblastoma, 21, 22 pancreatic cancer, 23 liver cancer, 24 lung cancer, 25–27 breast cancer, 28–31 esophageal cancer, 32 and colon cancer, 8, 33–35 have made the small molecule-mediated activation of procaspase-3 an attractive strategy for personalized medicine. 8–11 …”

Section: Introductionmentioning

confidence: 99%

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Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

et al. 2015

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Procaspase-Activating Compound 1 (PAC-1) is an ortho-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a Phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues was designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater AUC values for each of the four compounds, suggesting them as promising candidates for further development.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

et al. 2015

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“…Earlier this year, the Wolan group discovered a new compound that was capable of promoting the maturation of executioner procaspase-3 and -7 (Vickers et al, 2013). They used a clever fluorescence-polarization-based screen.…”

Section: Small-molecule Activators Of Caspasesmentioning

confidence: 99%

“…(A) Four small molecules have been reported to act as allosteric activators of procaspases; PAC-1 (Putt et al, 2006), 1541 (Wolan, Zorn, Gray, & Wells, 2009), compound-42 (Schipper, MacKenzie, Sharma, & Clark, 2011), and compound-2 (Vickers et al, 2013). (B) Mechanism of procaspase activation by 1541 nanofibrils.…”

Section: Figure 81mentioning

confidence: 99%

Turning ON Caspases with Genetics and Small Molecules

Morgan

Julien

Unger

et al. 2014

Regulated Cell Death Part A: Apoptotic Mechanisms

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Caspases, aspartate-specific cysteine proteases, have fate-determining roles in many cellular processes including apoptosis, differentiation, neuronal remodeling, and inflammation (for review, see Yuan & Kroemer, 2010). There are a dozen caspases in humans alone, yet their individual contributions toward these phenotypes are not well understood. Thus, there has been considerable interest in activating individual caspases or using their activity to drive these processes in cells and animals. We envision that such experimental control of caspase activity can not only afford novel insights into fundamental biological problems but may also enable new models for disease and suggest possible routes to therapeutic intervention. In particular, localized, genetic, and small-molecule-controlled caspase activation has the potential to target the desired cell type in a tissue. Suppression of caspase activation is one of the hallmarks of cancer and thus there has been significant enthusiasm for generating selective small-molecule activators that could bypass upstream mutational events that prevent apoptosis. Here, we provide a practical guide that investigators have devised, using genetics or small molecules, to activate specific caspases in cells or animals. Additionally, we show genetically controlled activation of an executioner caspase to target the function of a defined group of neurons in the adult mammalian brain.

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“…21 Recently, we described activity-based probes and inhibitors for caspase-3 that have >100-fold selectivity over the highly homologous caspase-7. 22,23 Another report details an inhibitor (M867) with 64-fold selectivity for caspase-3 over caspase-7. 24 Herein, we describe the discovery and characterization of CV8/9-AOMK and CV8/ 9-KE, which have nanomolar potency and >100-fold selectivity for inhibition of initiator caspases-8 and -9 over executioner caspases-3, -6, and -7 (Supplementary Figure S1).…”

mentioning

confidence: 99%

Selective Inhibition of Initiator versus Executioner Caspases Using Small Peptides Containing Unnatural Amino Acids

et al. 2014

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Caspases are fundamental to many essential biological processes, including apoptosis, differentiation, and inflammation. Unregulated caspase activity is also implicated in the development and progression of several diseases, such as cancer, neurodegenerative disorders, and sepsis. Unfortunately, it is difficult to determine exactly which caspase(s) of the 11 isoforms that humans express is responsible for specific biological functions. This lack of resolution is primarily due to highly homologous active sites and overlapping substrates. Currently available peptide-based inhibitors and probes are based on specificity garnered from peptide substrate libraries. For example, the canonical tetrapeptide LETD was discovered as the canonical sequence that is optimally recognized by caspase-8; however, LETD-based inhibitors and substrates promiscuously bind to other isoforms with equal affinity, including caspases-3, -6, and -9. In order to mitigate this problem, we report the identification of a new series of compounds that are >100-fold selective for inhibiting the initiator caspases-8 and -9 over the executioner caspases-3, -6, and -7.C aspases are a family of cysteine-dependent aspartatedirected proteases with 11 human isoforms that are traditionally known for their indispensible roles in the initiation (caspases-2, -8, -9, -10) and execution (caspases-3, -6, -7) of apoptosis. 1 Other family members, including caspases-1, -4, and -5, are important regulators of inflammation and induce pyroptotic cell death as a result of microbial infection. 2 Intriguingly, recent reports implicate caspase activity as being critical for a variety of other essential biological processes, such as DNA repair signaling and tumor suppression, 3 skeletal muscle differentiation, 4 B-cell proliferation, 5 dendritic pruning and neuronal plasticity, 6 embryonic stem cell differentiation through Nanog cleavage, 7 nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB) activation, 8 lymphocyte and monocyte differentiation and development, 9 and keratinocyte differentiation and skin barrier formation. 10 The utility of caspase-dependent proteolysis in an array of cellular functions is continually expanding, and additional caspase roles will likely be discovered with the development of highly potent and specific chemical inhibitors and probes.Active caspases have many significant irreversible consequences and as such are stored as inactive proenzymes, or procaspases, inside of the cell. 11 Intriguingly, several small molecules have been identified in high-throughput screens that promote executioner procaspase maturation using in vitro and in vivo models. 12−14 Aberrant caspase activity is implicated in the development and progression of several diseases, such as neurodegenerative disorders, 15 cancer, 16 cardiovascular disease, 17 and sepsis. 18 Moreover, caspases represent potential drug discovery targets for the treatment of these diseases, and it is therefore imperative to elucidate the exact biological roles of each i...

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Small‐Molecule Procaspase Activators Identified Using Fluorescence Polarization

Cited by 16 publications

References 31 publications

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

Turning ON Caspases with Genetics and Small Molecules

Selective Inhibition of Initiator versus Executioner Caspases Using Small Peptides Containing Unnatural Amino Acids

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