Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML)

doi:10.1016/j.ejphar.2021.173944

	Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML)
	Lu, Tingting 1,2,3,4; Cao, Jiangyan 1,2,3,5; Zou, Fengming 1,2,3,6; Li, Xixiang 1,2,3,6; Wang, Aoli 1,2,3,6; Wang, Wenliang 1,2,3; Liang, Huamin 1,2,3,6; Liu, Qingwang 1,2,3,6; Hu, Chen 1,2,3,6; Chen, Cheng 1,2,3
刊名	EUROPEAN JOURNAL OF PHARMACOLOGY
	2021-04-15
卷号	897
关键词	BCR-ABL ABL mutants Chronic myeloid leukemia Kinase inhibitor Imatinib resistance
ISSN号	0014-2999
DOI	10.1016/j.ejphar.2021.173944
通讯作者	Xia, Ruixiang(xrx2041@163.com) ; Liu, Qingsong(qsliu97@hmfl.ac.cn)
英文摘要	As the critical driving force for chronic myeloid leukemia (CML), BCR gene fused ABL kinase has been extensively explored as a validated target of drug discovery. Although imatinib has achieved tremendous success as the first-line treatment for CML, the long-term application ultimately leads to resistance, primarily via various acquired mutations occurring in the BCR-ABL kinase. Although dasatinib and nilotinib have been approved as second-line therapies that could overcome some of these mutants, the most prevalent gatekeeper T315I mutant remains unconquered. Here, we report a novel type II kinase inhibitor, CHMFL-48, that potently inhibits the wild-type BCR-ABL (wt) kinase as well as a panel of imatinib-resistant mutants, including T3151, F317L, E255K, Y253F, and M351T. CHMFL-48 displayed great inhibitory activity against ABL wt (IC50: 1 nM, 70-fold better than imatinib) and the ABL T315I mutant (IC50 : 0.8 nM, over 10,000-fold better than imatinib) in a biochemical assay and potently blocked the autophosphorylation of BCR-ABL wt and BCR-ABL mutants in a cellular context, which further affected downstream signalling mediators, including signal transducer and activator of transcription 5 (SLATS) and CRK like proto-oncogene (CRKL), and led to the cell cycle progression blockage as well as apoptosis induction. CHMFL-48 also exhibited great anti-leukemic efficacies in vivo in K562 cells and p210-T315I-transformed BaF3 cell-inoculated murine models. This discovery extended the pharmacological diversity of BCR-ABL kinase inhibitors and provided more potential options for anti-CML therapies.
资助项目	National Natural Science Foundation of China[81803366] ; National Natural Science Foundation of China[81903650] ; National Natural Science Foundation of China[81773777] ; Natural Science Foundation of Anhui Province[1808085MH268] ; Natural Science Foundation of Anhui Province[2008085MH274] ; Natural Science Foundation of Anhui Province[1908085QH348] ; China Postdoctoral Science Foundation[2019M652057] ; Postdoctoral Science Foundation of Anhui Province[2019B300] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037] ; Natural Science Foundation of the Anhui Higher Education Institutions of China[KJ2018ZD020] ; Research Fund for the Doctoral Program of Higher Education of China[20123420120011] ; CASHIPS Director's Fund[BJPY2019A03] ; Science and Technology Project from Jiaxing City[2017AY33019] ; Outstanding Talent Support Program in University of Anhui Province[gxyq2020018] ; Hefei Leading Talent[2018-1-006]
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000628752700010
资助机构	National Natural Science Foundation of China ; Natural Science Foundation of Anhui Province ; China Postdoctoral Science Foundation ; Postdoctoral Science Foundation of Anhui Province ; Frontier Science Key Research Program of CAS ; Natural Science Foundation of the Anhui Higher Education Institutions of China ; Research Fund for the Doctoral Program of Higher Education of China ; CASHIPS Director's Fund ; Science and Technology Project from Jiaxing City ; Outstanding Talent Support Program in University of Anhui Province ; Hefei Leading Talent
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/121122]
专题	中国科学院合肥物质科学研究院
通讯作者	Xia, Ruixiang; Liu, Qingsong
作者单位	1.Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Anhui, Peoples R China 2.CAS Key Lab High Magnet Field & Ion Beam Phys Bio, Hefei 230031, Anhui, Peoples R China 3.Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Hefei 230031, Anhui, Peoples R China 4.Anhui Univ Chinese Med, Key Lab Xinan Med, Minist Educ, Hefei 230012, Anhui, Peoples R China 5.Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China 6.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Anhui, Peoples R China 7.Anhui Med Univ, Dept Hematol, Affiliated Hosp 1, Hefei 230022, Anhui, Peoples R China 8.First Hosp Jiaxing, 1882 Zhonghuan South Rd, Jiaxing 314000, Zhejiang, Peoples R China 9.Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China 10.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei 230601, Anhui, Peoples R China
推荐引用方式 GB/T 7714	Lu, Tingting,Cao, Jiangyan,Zou, Fengming,et al. Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML)[J]. EUROPEAN JOURNAL OF PHARMACOLOGY,2021,897.
APA	Lu, Tingting.,Cao, Jiangyan.,Zou, Fengming.,Li, Xixiang.,Wang, Aoli.,...&Liu, Qingsong.(2021).Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML).EUROPEAN JOURNAL OF PHARMACOLOGY,897.
MLA	Lu, Tingting,et al."Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML)".EUROPEAN JOURNAL OF PHARMACOLOGY 897(2021).