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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, Xiaofei1,2; Liu, Xiaochuan1,3; Wang, Beilei1,2; Zou, Fengming1,2; Wang, Aoli1,4; Qi, Shuan1,2; Chen, Cheng1,2; Zhao, Zheng1,2; Wang, Wenchao1,2; Qi, Ziping1,2; Lv, Fengchao1,4; Hu, Zhenquan1,2; Wang, Li1,2; Zhang, Shanchun2,5; Liu, Qingsong1,2,4,6; Liu, Jing1,2
2016-03-10
Source PublicationJOURNAL OF MEDICINAL CHEMISTRY
AbstractStarting 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.
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
DOI10.1021/acs.jmedchem.5b01618
WOS KeywordCHRONIC MYELOGENOUS LEUKEMIA ; BCR-ABL ; TYROSINE KINASE ; T315I MUTANT ; IMATINIB ; RESISTANCE ; IDENTIFICATION ; TARGETS ; CANCER
Indexed BySCI
Language英语
Funding OrganizationHefei 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
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000372043400024
Citation statistics
Cited Times:9[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.hfcas.ac.cn:8080/handle/334002/22333
Collection中科院强磁场科学中心
Affiliation1.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
First Author AffilicationChinese Acad Sci, High Field Magnet Lab,Hefei 230031, Anhui, Peoples R China
Recommended Citation
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.
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