Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia

doi:10.1021/acs.jmedchem.5b01618

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	Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia
	Liang, Xiaofei 1,2; Liu, Xiaochuan 1,3; Wang, Beilei 1,2; Zou, Fengming 1,2; Wang, Aoli 1,4; Qi, Shuan 1,2; Chen, Cheng 1,2; Zhao, Zheng 1,2; Wang, Wenchao 1,2; Qi, Ziping 1,2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2016-03-10
卷号	59 期号:5 页码:1984-2004
DOI	10.1021/acs.jmedchem.5b01618
文献子类	Article
英文摘要	Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream Mediators such as STATS, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI(50) = 14 nM), KU812 (GI(50) = 25 nM), and MEG-01 (GI(50) = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.
WOS关键词	CHRONIC MYELOGENOUS LEUKEMIA ; BCR-ABL ; TYROSINE KINASE ; T315I MUTANT ; IMATINIB ; RESISTANCE ; IDENTIFICATION ; TARGETS ; CANCER
WOS研究方向	Pharmacology & Pharmacy
语种	英语
WOS记录号	WOS:000372043400024
资助机构	Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; 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 ; 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) ; 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) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; Hefei Science Center of CAS (SRG-HSC)(2015SRG-HSC022) ; 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 ; 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) ; 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) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; National Natural Science Foundation of China(81402797) ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China ; Top-Notch Young Talents Program of China
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/22333]
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 Field Magnet Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China 2.CHMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China 3.Univ Sci & Technol China, Dept Chem, Hefei 230036, Anhui, Peoples R China 4.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China 5.Hefei Cosource Med Technol Co LTD, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China 6.Chinese Acad Sci, Hefei Sci Ctr, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
推荐引用方式 GB/T 7714	Liang, Xiaofei,Liu, Xiaochuan,Wang, Beilei,et al. Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(5):1984-2004.
APA	Liang, Xiaofei.,Liu, Xiaochuan.,Wang, Beilei.,Zou, Fengming.,Wang, Aoli.,...&Liu, Jing.(2016).Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia.JOURNAL OF MEDICINAL CHEMISTRY,59(5),1984-2004.
MLA	Liang, Xiaofei,et al."Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia".JOURNAL OF MEDICINAL CHEMISTRY 59.5(2016):1984-2004.