Abstract
We report the discovery of a novel series of 1,5-bisphenylpyrazoles as potent MALT1 inhibitors. Structure-activity relationship exploration of a hit compound led to a potent MALT1 inhibitor. Compound 33 showed strong activity against MALT1 (IC50: 0.49 μM), potent cellular activity (NF-κB inhibition and inhibition of IL2 production), and high selectivity against caspase-3, -8, and -9. The results of a kinetics study suggest that compound 33 is a non-competitive inhibitor of MALT1 protein.
Keywords:
Allosteric inhibitors; MALT1; Paracaspase; Structure activity relationship.
Copyright © 2021 Elsevier Ltd. All rights reserved.
MeSH terms
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Allosteric Regulation / drug effects
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacology*
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Dose-Response Relationship, Drug
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Humans
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Molecular Structure
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / antagonists & inhibitors*
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / metabolism
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Structure-Activity Relationship
Substances
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Cysteine Proteinase Inhibitors
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Pyrazoles
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MALT1 protein, human
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein