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  4. 中科院强磁场科学中心
Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia

文献类型：期刊论文

作者Wu, H.1,2; Hu, C.1; Wang, A.1,2; Weisberg, E. L.3; Chen, Y.1; Yun, C-H4; Wang, W.1; Liu, Y.3; Liu, X.1,2; Tian, B.5
刊名LEUKEMIA
出版日期2016
卷号30期号:1页码:173-181
DOI10.1038/leu.2015.180
文献子类Article
英文摘要Bruton's tyrosine kinase (BTK) kinase is a member of the TEC kinase family and is a key regulator of the B-cell receptor (BCR)-mediated signaling pathway. It is important for B-cell maturation, proliferation, survival and metastasis. Pharmacological inhibition of BTK is clinically effective against a variety of B-cell malignances, such as mantle cell lymphoma, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and activated B-cell-diffuse large B-cell lymphoma. MNK kinase is one of the key downstream regulators in the RAF-MEK-ERK signaling pathway and controls protein synthesis via regulating the activity of eIF4E. Inhibition of MNK activity has been observed to moderately inhibit the proliferation of AML cells. Through a structure-based drug-design approach, we have discovered a selective and potent BTK/MNK dual kinase inhibitor (QL-X-138), which exhibits covalent binding to BTK and noncovalent binding to MNK. Compared with the BTK kinase inhibitor (PCI-32765) and the MNK kinase inhibitor (cercosporamide), QL-X-138 enhanced the antiproliferative efficacies in vitro against a variety of B-cell cancer cell lines, as well as AML and CLL primary patient cells, which respond moderately to BTK inhibitor in vitro. The agent can effectively arrest the growth of lymphoma and leukemia cells at the G0-G1 stage and can induce strong apoptotic cell death. These primary results demonstrate that simultaneous inhibition of BTK and MNK kinase activity might be a new therapeutic strategy for B-cell malignances.
WOS关键词BRUTONS TYROSINE KINASE ; MANTLE-CELL LYMPHOMA ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; X-LINKED AGAMMAGLOBULINEMIA ; ACUTE MYELOID-LEUKEMIA ; CANCER-THERAPY ; TARGETING BTK ; IBRUTINIB ; TRANSLATION ; EIF4E
WOS研究方向Oncology ; Hematology
语种英语
WOS记录号WOS:000369481600020
资助机构Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022)
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/22282]  
专题合肥物质科学研究院_中科院强磁场科学中心
作者单位1.Chinese Acad Sci, High Magnet Field Lab, 350 Shushanhu Rd,Mailbox 1110, Hefei 230031, Anhui, Peoples R China
2.Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China
3.Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA
4.Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave,SGM 628, Boston, MA 02115 USA
5.Capital Med Univ, Beijing Tongren Hosp, Beijing Ophthalmol & Visual Sci Key Lab, Beijing Tongren Eye Ctr, Beijing, Peoples R China
6.Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Dept Lymphoma SinoUS Ctr Lymphoma & Leukemia, Tianjin, Peoples R China
7.Chinese Acad Sci, Hefei Sci Ctr, Hefei, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Wu, H.,Hu, C.,Wang, A.,et al. Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia[J]. LEUKEMIA,2016,30(1):173-181.
APA Wu, H..,Hu, C..,Wang, A..,Weisberg, E. L..,Chen, Y..,...&Liu, Q..(2016).Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia.LEUKEMIA,30(1),173-181.
MLA Wu, H.,et al."Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia".LEUKEMIA 30.1(2016):173-181.

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来源：合肥物质科学研究院

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