Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors

被引：13

作者：

Wang, Beilei ^{[1
,2
]}

Deng, Yuanxin ^{[1
,2
]}

Chen, Yongfei ^{[1
]}

Yu, Kailin ^{[1
,2
]}

Wang, Aoli ^{[1
,2
]}

Liang, Qianmao ^{[1
]}

Wang, Wei ^{[1
,3
]}

Chen, Cheng ^{[1
,2
]}

Wu, Hong ^{[1
,3
]}

Hu, Chen ^{[1
,2
]}

Miao, Weili ^{[4
]}

Hur, Wooyoung ^{[5
]}

Wang, Wenchao ^{[1
,2
]}

Hu, Zhenquan ^{[1
,3
]}

Weisberg, Ellen L. ^{[5
]}

Wang, Jinhua ^{[6
]}

Ren, Tao ^{[7
]}

Wang, Yinsheng ^{[4
]}

Gray, Nathanael S. ^{[6
]}

Liu, Qingsong ^{[1
,2
,3
,7
,8
]}

Liu, Jing ^{[1
,3
]}

机构：

[1] Chinese Acad Sci, High Field Magnet Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China

[2] Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China

[3] CHMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China

[4] Univ Calif Riverside, Dept Chem, 900 Univ Ave, Riverside, CA 92521 USA

[5] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA

[6] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave,SGM 628, Boston, MA 02115 USA

[7] Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China

[8] Chinese Acad Sci, Hefei Sci Ctr, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 137卷

基金：

中国国家自然科学基金;

关键词：

BTK; Kinase inhibitor; Irreversible inhibitor; Structure-activity relationship; B-Cell lymphoma; X-LINKED AGAMMAGLOBULINEMIA; DISCOVERY; GENE; EXPRESSION; LYMPHOMA; LEUKEMIA; MUTANT; CELLS;

D O I：

10.1016/j.ejmech.2017.06.016

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed BTK inhibitors, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound 18 (CHMFL-BTK-11). Kinetic analysis of compound 18 revealed an irreversible binding efficacy (k(inact)/K-i) of 0.01 mu M(-1)s(-1). Compound 18 potently inhibited BTK kinase Y223 auto-phosphorylation (EC50 < 100 nM), arrested cell cycle in G0/G1 phase, and induced apoptosis in Ramos, MOLM13 and Pfeiffer cells. We believe these features would make 18 a good pharmacological tool for studying BTK-related pathologies. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：545 / 557

页数：13

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