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Discovery and characterization of a novel highly potent and selective type II native and drug-resistant V299L mutant BCR-ABL inhibitor (CHMFL-ABL-039) for Chronic Myeloid Leukemia (CML)

文献类型：期刊论文

作者Wu, Jiaxin1,2; Wang, Aoli1; Li, Xixiang1,3; Chen, Cheng1,2; Qi, Ziping1,3; Hu, Chen1,2; Wang, Wenliang1,2; Wu, Hong1; Huang, Tao4; Zhao, Ming4
刊名CANCER BIOLOGY & THERAPY
出版日期2019-06-03
卷号20期号:6页码:877-885
ISSN号1538-4047
关键词BCR-ABL PDGFR chronic myeloid leukemia kinase inhibitor
DOI10.1080/15384047.2019.1579958
通讯作者Wu, Jiaxin(qsliu97@hmfl.ac.cn) ; Xia, Ruixiang(xrx2041@163.com) ; Liu, Jing(jingliu@hmfl.ac.cn)
英文摘要BCR fused ABL kinase is the critical driving oncogene for chronic myeloid leukemia (CML) and has been extensively studied as the drug discovery target in the past decade. The successful introduction of tyrosine kinase inhibitors (TKI) such as Imatinib, Dasatinib and Bosutinib has greatly improved the CML patient survival rate. However, upon the chronic treatment, a variety of TKI resistant mutants, such as the V299L mutant which has been found in more and more patients with the high-throughput sequencing technology, are observed, although the incidence is still considered rare compared to the more prevalent gatekeeper T315I mutant. However, with the progress of the precision medicine concept, the rare mutation (or the orphan drug target) has attracted more and more attention. Here we report a novel type II BCR-ABL kinase inhibitor, CHMFL-ABL-039, which not only displayed great potency (IC50: 7.9 nM) and selectivity (S score (1) = 0.02) against native ABL kinase among other kinases in the kinome, but also exhibited great potency (IC50: 27.9 nM) and selectivity against Imatinib-resistant V299L mutant among other frequently observed ABL kinase mutants. CHMFL-ABL-039 has demonstrated greater efficacies than Imatinib regarding to the anti-proliferation, inhibition of the signaling pathway, arrest of cell cycle progression, induction of apoptosis in vitro and suppression of the tumor progression in vivo in the native and V299L mutated BCR-ABL kinase-driven cells/xenograft models. It would be a useful pharmacological tool to study the TKI resistant ABL V299L mutant-mediated pathology and provide a potential precise treatment approach for this orphan CML subtype in the precision medicine era.
WOS关键词DUAL KINASE INHIBITOR ; AMN107 ; BIND
资助项目National Natural Science Foundation of China[81471773] ; National Natural Science Foundation of China[81473088] ; National Natural Science Foundation of China[2140207] ; Natural Science Foundation of Anhui province[1508085MB23] ; Natural Science Foundation of Anhui province[1608085QH180] ; Natural Science Foundation of Anhui province[1708085MH208]
WOS研究方向Oncology
语种英语
出版者TAYLOR & FRANCIS INC
WOS记录号WOS:000461971600001
资助机构National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province ; Natural Science Foundation of Anhui province
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/38436]  
专题合肥物质科学研究院_中科院强磁场科学中心
合肥物质科学研究院_合肥创新院
通讯作者Wu, Jiaxin; Xia, Ruixiang; Liu, Jing
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, Anhui, Peoples R China
3.CHMFL HCMTC Target Therapy Joint Lab, Hefei, Anhui, Peoples R China
4.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei, Anhui, Peoples R China
5.Anhui Med Univ, Dept Hematol, Hosp 1, Hefei, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Jiaxin,Wang, Aoli,Li, Xixiang,et al. Discovery and characterization of a novel highly potent and selective type II native and drug-resistant V299L mutant BCR-ABL inhibitor (CHMFL-ABL-039) for Chronic Myeloid Leukemia (CML)[J]. CANCER BIOLOGY & THERAPY,2019,20(6):877-885.
APA Wu, Jiaxin.,Wang, Aoli.,Li, Xixiang.,Chen, Cheng.,Qi, Ziping.,...&Liu, Jing.(2019).Discovery and characterization of a novel highly potent and selective type II native and drug-resistant V299L mutant BCR-ABL inhibitor (CHMFL-ABL-039) for Chronic Myeloid Leukemia (CML).CANCER BIOLOGY & THERAPY,20(6),877-885.
MLA Wu, Jiaxin,et al."Discovery and characterization of a novel highly potent and selective type II native and drug-resistant V299L mutant BCR-ABL inhibitor (CHMFL-ABL-039) for Chronic Myeloid Leukemia (CML)".CANCER BIOLOGY & THERAPY 20.6(2019):877-885.

入库方式： OAI收割

来源：合肥物质科学研究院

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