Abstract
MALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series. In human T-cells and B-cell lymphoma lines, MLT-231 potently and selectively inhibits the proteolytic activity of MALT1 in NF-κB-dependent assays. Both in vitro and in vivo profiling of MLT-231 support further optimization of this in vivo tool compound toward preclinical characterization.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Caspase Inhibitors / chemical synthesis
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Caspase Inhibitors / pharmacology
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Caspase Inhibitors / therapeutic use*
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Drug Discovery
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Female
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Humans
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Immunity, Humoral / drug effects
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Male
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Mice, Inbred BALB C
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Molecular Structure
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / antagonists & inhibitors*
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Neoplasms / drug therapy*
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Pyrazoles / chemical synthesis
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Pyrazoles / pharmacology
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Pyrazoles / therapeutic use
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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T-Lymphocytes / drug effects
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Urea / analogs & derivatives*
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Urea / pharmacology
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Urea / therapeutic use*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Caspase Inhibitors
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Pyrazoles
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Pyrimidines
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Urea
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MALT1 protein, human
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Malt1 protein, mouse
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein