Abstract
The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment.
Keywords:
B-cell lymphoma; BCR signaling; Btk; irreversible inhibitor; targeted therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / chemistry
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Acrylamides / pharmacology*
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Adenine / analogs & derivatives
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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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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Apoptosis / genetics
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Benzamides / chemistry
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Benzamides / pharmacology*
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Blotting, Western
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Caspases / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Cell Survival / drug effects
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Cell Survival / genetics
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Gene Expression Profiling / methods
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Lymphoma, B-Cell / drug therapy*
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism
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Mice, SCID
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Microscopy, Confocal
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Molecular Structure
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Piperidines
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Pyrazoles / pharmacology
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Pyrimidines / pharmacology
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RNA Interference
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Receptors, Antigen, B-Cell / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Acrylamides
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Antineoplastic Agents
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Benzamides
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PLS-123
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Piperidines
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Receptors, Antigen, B-Cell
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ibrutinib
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human
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PTPN11 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Caspases
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Adenine
Associated data
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GEO/GSE65816
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GEO/GSE65817