title: Discovery of a series of 2,5-diaminopyrimidine covalent irreversible inhibitors of Bruton's tyrosine kinase with in vivo antitumor activity.
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.
authors.affiliation: Key Laboratory of Chemical Genomics, Key Laboratory of Structural Biology, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University , Shenzhen, 518055, China.
authors.forename: Xitao
authors.initials: X
authors.lastname: Li
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zuo
authors.forename: Guanghui
authors.initials: G
authors.lastname: Tang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xueying
authors.initials: X
authors.lastname: Wang
authors.forename: Tianlin
authors.initials: T
authors.lastname: Guo
authors.forename: Mengying
authors.initials: M
authors.lastname: Xia
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.forename: Zhengying
authors.initials: Z
authors.lastname: Pan
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D064593:Heterografts; D006801:Humans; D016393:Lymphoma, B-Cell; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D001549:Benzamides; C000591339:N-(2-(3-acrylamidophenylamino)pyrimidin-5-yl)-2-methyl-5-(3-(trifluoromethyl)benzamido)benzamide; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse