Abstract
Human caseinolytic protease P (hClpP) is important for degradation of misfolded proteins in the mitochondrial unfolded protein response. We here introduce tailored hClpP inhibitors that utilize a steric discrimination in their core naphthofuran scaffold to selectively address the human enzyme. This novel inhibitor generation exhibited superior activity compared to previously introduced beta-lactones, optimized for bacterial ClpP. Further insights into the bioactivity and binding to cellular targets were obtained via chemical proteomics as well as proliferation- and migration studies in cancer cells.
MeSH terms
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ATPases Associated with Diverse Cellular Activities / antagonists & inhibitors
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Benzofurans / chemical synthesis
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Benzofurans / chemistry
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Benzofurans / pharmacology*
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Cell Line, Tumor
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Cell Movement / drug effects
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Drug Design
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Endopeptidase Clp / antagonists & inhibitors
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Escherichia coli / enzymology
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Escherichia coli Proteins / antagonists & inhibitors
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Humans
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Kallikreins / antagonists & inhibitors*
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Molecular Chaperones / antagonists & inhibitors
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Staphylococcus aureus / enzymology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Benzofurans
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Escherichia coli Proteins
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Molecular Chaperones
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Protease Inhibitors
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Kallikreins
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Endopeptidase Clp
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ClpX protein, E coli
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ATPases Associated with Diverse Cellular Activities