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Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)

文献类型：期刊论文

作者Liu, Feiyang1,2; Wang, Beilei1,3; Wang, Qiang1,3; Qi, Ziping1,3; Chen, Cheng1,3; Kong, Lu-Lu4,5; Chen, Ji-Yun4,5; Liu, Xiaochuan1,6; Wang, Aoli1,2; Hu, Chen1,2
刊名ONCOTARGET
出版日期2016-07-19
卷号7期号:29页码:45562-45574
关键词Bcr-abl Pdgfr Chronic Myeloid Leukemia Kinase Inhibitor
DOI10.18632/oncotarget.10037
文献子类Article
英文摘要BCR gene fused ABL kinase is the critical driving force for the Philadelphia Chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) and has been extensively explored as a drug target. With a structure-based drug design approach we have discovered a novel inhibitor CHMFL-074, that potently inhibits both the native and a variety of clinically emerged mutants of BCR-ABL kinase. The X-ray crystal structure of CHMFL-074 in complex with ABL1 kinase (PDB ID: 5HU9) revealed a typical type II binding mode (DFG-out) but relatively rare hinge binding. Kinome wide selectivity profiling demonstrated that CHMFL-074 bore a high selectivity (S score(1) = 0.03) and potently inhibited ABL1 kinase (IC50 : 24 nM) and PDGFR alpha/beta (IC50 : 71 nM and 88 nM). CHMFL-074 displayed strong anti-proliferative efficacy against BCR-ABL-driven CML cell lines such as K562 (GI(50) : 56 nM), MEG-01 (GI(50) : 18 nM) and KU812 (GI(50) : 57 nM). CHMFL-074 arrested cell cycle into the G0/G1 phase and induced apoptosis in the Ph+ CML cell lines. In addition, it potently inhibited the CML patient primary cell's proliferation but did not affect the normal bone marrow cells. In the CML cell K562 inoculated xenograft mouse model, oral administration of 100 mg/kg/d of CHMFL-074 achieved a tumor growth inhibition (TGI) of 65% without exhibiting apparent toxicity. As a potential drug candidate for fighting CML, CHMFL-074 is under extensive preclinical safety evaluation now.
WOS关键词IMATINIB ; RESISTANCE ; ALGORITHM
WOS研究方向Oncology ; Cell Biology
语种英语
WOS记录号WOS:000385402300055
资助机构Joint Fund of Research on Major Science Facilities ; Joint Fund of Research on Major Science Facilities ; Joint Fund of Research on Major Science Facilities ; Joint Fund of Research on Major Science Facilities ; Key Program ; Key Program ; Key Program ; Key Program ; NSFC(U1432250) ; NSFC(U1432250) ; NSFC(U1432250) ; NSFC(U1432250) ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; China " Thousand Talents Program" ; China " Thousand Talents Program" ; China " Thousand Talents Program" ; China " Thousand Talents Program" ; "Hundred Talents Program" of The Chinese Academy of Sciences ; "Hundred Talents Program" of The Chinese Academy of Sciences ; "Hundred Talents Program" of The Chinese Academy of Sciences ; "Hundred Talents Program" of The Chinese Academy of Sciences ; 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) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; Ministry of Education of China(NCET-12-0013) ; Ministry of Education of China(NCET-12-0013) ; Ministry of Education of China(NCET-12-0013) ; Ministry of Education of China(NCET-12-0013) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; Joint Fund of Research on Major Science Facilities ; Joint Fund of Research on Major Science Facilities ; Joint Fund of Research on Major Science Facilities ; Joint Fund of Research on Major Science Facilities ; Key Program ; Key Program ; Key Program ; Key Program ; NSFC(U1432250) ; NSFC(U1432250) ; NSFC(U1432250) ; NSFC(U1432250) ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; China " Thousand Talents Program" ; China " Thousand Talents Program" ; China " Thousand Talents Program" ; China " Thousand Talents Program" ; "Hundred Talents Program" of The Chinese Academy of Sciences ; "Hundred Talents Program" of The Chinese Academy of Sciences ; "Hundred Talents Program" of The Chinese Academy of Sciences ; "Hundred Talents Program" of The Chinese Academy of Sciences ; 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) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; Ministry of Education of China(NCET-12-0013) ; Ministry of Education of China(NCET-12-0013) ; Ministry of Education of China(NCET-12-0013) ; Ministry of Education of China(NCET-12-0013) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769)
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/30132]  
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, Hefei 230031, Anhui, Peoples R China
2.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
3.CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China
4.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci,Dept Biophys, Beijing Key Lab Tumor Syst Biol,Inst Syst Biomed, Beijing 100191, Peoples R China
5.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Mol & Translat Med, Beijing 100191, Peoples R China
6.Univ Sci & Technol China, Dept Chem, Hefei 230036, Anhui, Peoples R China
7.Anhui Med Univ, Hosp 2, Dept Hematol, Hefei 230601, Anhui, Peoples R China
8.Anhui Med Univ, Hematol Res Ctr, Hefei 230601, Anhui, Peoples R China
9.Hefei Cosource Med Technol Co LTD, Hefei 230031, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Feiyang,Wang, Beilei,Wang, Qiang,et al. Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)[J]. ONCOTARGET,2016,7(29):45562-45574.
APA Liu, Feiyang.,Wang, Beilei.,Wang, Qiang.,Qi, Ziping.,Chen, Cheng.,...&Liu, Qingsong.(2016).Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML).ONCOTARGET,7(29),45562-45574.
MLA Liu, Feiyang,et al."Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)".ONCOTARGET 7.29(2016):45562-45574.

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来源：合肥物质科学研究院

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