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学科主题: 临床医学
题名:
Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma
作者: Ding, Ning1; Li, Xitao2; Shi, Yunfei3; Ping, Lingyan1; Wu, Lina4; Fu, Kai5; Feng, Lixia1; Zheng, Xiaohui1; Song, Yuqin1; Pan, Zhengying2; Zhu, Jun1
关键词: BCR signaling ; Btk ; irreversible inhibitor ; targeted therapy ; B-cell lymphoma
刊名: ONCOTARGET
发表日期: 2015-06-20
卷: 6, 期:17, 页:15122-15136
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Oncology ; Cell Biology
研究领域[WOS]: Oncology ; Cell Biology
关键词[WOS]: CHRONIC LYMPHOCYTIC-LEUKEMIA ; TYROSINE KINASE INHIBITOR ; IN-VIVO ; THERAPEUTIC TARGET ; RECEPTOR ; PCI-32765 ; IBRUTINIB ; PATHWAY ; MALIGNANCIES ; ACTIVATION
英文摘要:

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.

语种: 英语
所属项目编号: 81470368 ; 81201873 ; 2013CB910704 ; 2011CB504303 ; 7132050 ; JCYJ20140509093817688 ; 81373270
项目资助者: NSFC ; 973 program ; Beijing Natural Science Foundation ; Shenzhen Science and Technology Innovation Committee ; National Natural Science Foundation of China ; "985" Basic Research Fund from Peking University
WOS记录号: WOS:000359010700037
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/64721
Appears in Collections:北京大学临床肿瘤学院_病理科_期刊论文

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作者单位: 1.Peking Univ, Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Minist Educ,Dept Lymphoma, Beijing 100871, Peoples R China
2.Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, Key Lab Chem Genom, Shenzhen, Peoples R China
3.Peking Univ, Canc Hosp & Inst, Dept Pathol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100871, Peoples R China
4.Peking Univ, Canc Hosp & Inst, Cent Lab, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100871, Peoples R China
5.Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA

Recommended Citation:
Ding, Ning,Li, Xitao,Shi, Yunfei,et al. Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma[J]. ONCOTARGET,2015,6(17):15122-15136.
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