Abstract
Bruton's tyrosine kinase (Btk) is an attractive drug target for treating several B-cell lineage cancers. Ibrutinib is a first-in-class covalent irreversible Btk inhibitor and has demonstrated impressive effects in multiple clinical trials. Herein, we present a series of novel 2,5-diaminopyrimidine covalent irreversible inhibitors of Btk. Compared with ibrutinib, these inhibitors exhibited a different selectivity profile for the analyzed kinases as well as a dual-action mode of inhibition of both Btk activation and catalytic activity, which counteracts a negative regulation loop for Btk. Two compounds from this series, 31 and 38, showed potent antiproliferative activities toward multiple B-cell lymphoma cell lines, including germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) cells. In addition, compound 31 significantly prevented tumor growth in a mouse xenograft model.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / chemical synthesis*
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Acrylamides / chemistry
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Acrylamides / pharmacology
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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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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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Benzamides / pharmacology
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Female
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Heterografts
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Humans
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Lymphoma, B-Cell
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Mice, Inbred ICR
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Mice, SCID
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Neoplasm Transplantation
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Phosphorylation
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Structure-Activity Relationship
Substances
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Acrylamides
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Antineoplastic Agents
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Benzamides
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N-(2-(3-acrylamidophenylamino)pyrimidin-5-yl)-2-methyl-5-(3-(trifluoromethyl)benzamido)benzamide
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Pyrimidines
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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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Btk protein, mouse