Screening for Caspase-3 Inhibitors: A New Class of Potent Small-Molecule Inhibitors of Caspase-3

Okun, Ilya; Malarchuk, Sergei; Dubrovskaya, E. S.; Khvat, Alexander; Ткаченко, С. Е.; Kysil, Volodymyr; Ilyin, A.P.; Kravchenko, Dmitry V.; Prossnitz, Eric R.; Sklar, Larry A.; Ivachtchenko, Alexandre V.

doi:10.1177/1087057105285048

Cited by 20 publications

(20 citation statements)

References 27 publications

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“…From the data shown in Figure 3, time-dependent inhibition of caspase-3 activity suggests irreversible interaction of compounds with caspase-3 enzyme and is similar to the reported caspase inhibitor IDN6556 [6,10,13]. …”

Section: Resultssupporting

confidence: 79%

“…The fluorescence signal as well as signal to noise ratio was optimal at 10 U of caspase-3 and 10-μM substrate. Substrate exhibited Michaelis-Menten constant of 11.7 μM and was comparable to the published data [10]. The caspase-3 assay was validated using reference inhibitor (IDN6556) across all plates and different experiments [10-12].…”

Section: Resultssupporting

confidence: 66%

“…The ability of NCEs to inhibit the activity of human recombinant caspases as well as other proteases was determined using a standard fluorometric microplate assay as described in [1,10]. The assay buffer contained 25 mM sodium HEPES, 50 mM KCl, 0.1% CHAPS, and 1 mM β-mercaptoethanol, pH7.4.…”

Section: Methodsmentioning

confidence: 99%

“…The anti-apototic assay was done as described in [10]. Briefly, Jurkat (human T-cell leukemia) cell line (ATCC) was cultured in RPMI-1640 medium with l -glutamine and supplemented with 10% fetal bovine serum and antibiotic solution.…”

Section: Methodsmentioning

confidence: 99%

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Discovery of indole tetrafluorophenoxymethylketone-based potent novel small molecule inhibitors of caspase-3

Samiulla

Naidu

Rao

et al. 2012

Organic and Medicinal Chemistry Letters

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BackgroundCaspase-3 inhibition has been demonstrated to be therapeutically effective in moderating excessive programmed cell death. Interest in caspase-3 as a therapeutic target has led many to pursue the development of inhibitors. To date, only a few series of non-peptide inhibitors have been described, and these have limitations on their drug-like properties.MethodsHere, we report the screening of 70 novel small molecules against the caspase-3 enzyme which belongs to four different series (indole fluoromethylketone, indole difluoro and tetrafluorophenoxymethylketone, and oxalamide). Selected molecules were subjected for counter-screening, cell-based, ADME/PK assays in order to understand the potency and drug-like properties.ResultsThe screening yielded series of hits with IC50 values ranging from 0.11 to 10 μM with reasonable SAR, irreversible mode of inhibition, and reasonable selectivity against other proteases including caspase-1, cathepsin B and D, and thrombin. On the basis of in vitro profile, the selected molecules were evaluated for their drug-like properties. Among the compounds evaluated, compound 3D exhibited good solubility, low permeability, interaction with efflux pump, and low potential for CYP450 drug-drug interaction. After intravenous administration, compound 3D showed low clearance (588 ml/hr/kg), medium volume of distribution, and good oral bioavailability (90%).ConclusionsThese results support further advancement of compound 3D in different apoptotic models to develop as a new anti-apoptotic agent in relevant disease conditions.

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Section: Resultssupporting

confidence: 79%

Section: Resultssupporting

confidence: 66%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of indole tetrafluorophenoxymethylketone-based potent novel small molecule inhibitors of caspase-3

Samiulla

Naidu

Rao

et al. 2012

Organic and Medicinal Chemistry Letters

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“…355 Next, this pool of compounds was tested against caspase-3. One of the selection criteria was based on the warhead concept, which from prior art should possess an electrophilic moiety.…”

Section: Caspase Inhibitorsmentioning

confidence: 99%

Small Molecule Active Site Directed Tools for Studying Human Caspases

et al. 2015

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Caspases are proteases of clan CD and were described for the first time more than two decades ago. They play critical roles in the control of regulated cell death pathways including apoptosis and inflammation. Due to their involvement in the development of various diseases like cancer, neurodegenerative diseases or autoimmune disorders, caspases have been intensively investigated as potential drug targets, both in academic and industrial laboratories. This review presents a thorough, deep, and systematic assessment of all technologies developed over the years for the investigation of caspase activity and specificity using substrates and inhibitors, as well as activity based probes, which in recent years have attracted considerable interest due to their usefulness in the investigation of biological functions of this family of enzymes.

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Downregulation of SF3B2 protects CNS neurons in models of multiple sclerosis

Jeong

Rajbhandari

Kim

et al. 2022

Ann Clin Transl Neurol

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Objective Neurodegeneration induced by inflammatory stress in multiple sclerosis (MS) leads to long‐term neurological disabilities that are not amenable to current immunomodulatory therapies. Methods and Results Here, we report that neuronal downregulation of Splicing factor 3b subunit 2 (SF3B2), a component of U2 small nuclear ribonucleoprotein (snRNP), preserves retinal ganglion cell (RGC) survival and axonal integrity in experimental autoimmune encephalomyelitis (EAE)‐induced mice. By employing an in vitro system recapitulating the inflammatory environment of MS lesion, we show that when SF3B2 levels are downregulated, cell viability and axon integrity are preserved in cortical neurons against inflammatory toxicity. Notably, knockdown of SF3B2 suppresses the expression of injury‐response and necroptosis genes and prevents activation of Sterile Alpha and TIR Motif Containing 1 (Sarm1), a key enzyme that mediates programmed axon degeneration. Interpretation Together, these findings suggest that the downregulation of SF3B2 is a novel potential therapeutic target to prevent secondary neurodegeneration in MS.

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Screening for Caspase-3 Inhibitors: A New Class of Potent Small-Molecule Inhibitors of Caspase-3

Cited by 20 publications

References 27 publications

Discovery of indole tetrafluorophenoxymethylketone-based potent novel small molecule inhibitors of caspase-3

Discovery of indole tetrafluorophenoxymethylketone-based potent novel small molecule inhibitors of caspase-3

Small Molecule Active Site Directed Tools for Studying Human Caspases

Downregulation of SF3B2 protects CNS neurons in models of multiple sclerosis

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