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J Med Chem. 2014 Jun 26;57(12):5112-28. doi: 10.1021/jm4017762. Epub 2014 Jun 10.

Discovery of a series of 2,5-diaminopyrimidine covalent irreversible inhibitors of Bruton's tyrosine kinase with in vivo antitumor activity.

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Key Laboratory of Chemical Genomics, Key Laboratory of Structural Biology, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University , Shenzhen, 518055, China.


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.

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