Abstract
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.
Highlights
Caspase-3 inhibition has been demonstrated to be therapeutically effective in moderating excessive programmed cell death
A major biochemical pathway involved in the apoptosis includes a family of proteases, known as caspases, which act in a cascade to activate downstream caspases responsible for breakdown or cleavage of key cellular substrates required for normal cellular fashion, including structural proteins in the
As the active site of caspase-3 contains a sulfhydryl moiety necessary for its catalytic activity, we focused on molecules with the warheads capable of reacting with the cysteinyl thiols
Summary
Caspase-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. Apoptosis or programmed cell death is a critical cellular process in normal development and homeostasis of multicellular organisms. A major biochemical pathway involved in the apoptosis includes a family of proteases, known as caspases, which act in a cascade to activate downstream caspases responsible for breakdown or cleavage of key cellular substrates required for normal cellular fashion, including structural proteins in the Caspases are found practically in all organisms from Caenorhabditis elegans to humans. Activation of caspase-3 is a key event integrating upstream signals into final execution of cell death [4]
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