中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors

文献类型:期刊论文

作者Chan, Shingpan2,3; Zhang, Yunong2,3; Wang, Jie2,3; Yu, Qiuchun2,3; Peng, Xia4; Zou, Jian2,3; Zhou, Licheng1; Tan, Li2,3; Duan, Yunxin2,3; Zhou, Yang2,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-11-24
卷号65期号:22页码:15374-15390
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c01346
通讯作者Ai, Jing(jai@simm.ac.cn) ; Wang, Zhen(wangz@sioc.ac.cn) ; Ren, Xiaomei(ren_xiaomei@jnu.edu.cn) ; Zhang, Zhang(zhang_zhang@jnu.edu.cn) ; Ding, Ke(dingke@jnu.edu.cn)
英文摘要The receptor tyrosine kinase AXL is a promising target for anticancer drug discovery. Herein, we describe the discovery of 3-aminopyrazole derivatives as new potent and selective AXL kinase inhibitors. One of the representative compounds, 6li, potently inhibited AXL enzymatic activity with an IC50 value of 1.6 nM, and tightly bound with AXL protein with a Kd value of 0.26 nM, while was obviously less potent against most of the 403 wild-type kinases evaluated. Cell-based assays demonstrated that compound 6li potently inhibited AXL signaling, suppressed Ba/F3-TEL-AXL cell proliferation, reversed TGF-beta 1-induced epithelial-mesenchymal transition, and dose-dependently impeded cancer cell migration and invasion. Compound 6li also showed reasonable pharmacokinetic properties in rats and exhibited significant in vivo antitumor efficacy in a xenograft model of highly metastatic murine breast cancer 4T1 cells. Taken together, this study provides a new potent and selective AXL inhibitor for further anticancer drug discovery.
WOS关键词RECEPTOR TYROSINE KINASE ; THERAPEUTIC TARGET ; MYELOID-LEUKEMIA ; CANCER-CELLS ; RESISTANCE ; PROLIFERATION ; CABOZANTINIB ; ACTIVATION ; PATHWAY ; PROFILE
资助项目Ministry of Science and Technology of the People's Republic of China[SQ2019YFE010401] ; National Natural Science Foundation of China[81874284] ; National Natural Science Foundation of China[818201029] ; National Natural Science Foundation of China[8182010804] ; National Natural Science Foundation of China[22037003] ; National Natural Science Foundation of China[81973158] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02] ; State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000891373700001
源URL[http://119.78.100.183/handle/2S10ELR8/304419]  
专题新药研究国家重点实验室
通讯作者Ai, Jing; Wang, Zhen; Ren, Xiaomei; Zhang, Zhang; Ding, Ke
作者单位1.Chinese Acad Sci, Shanghai Inst Organ Chem, Ctr Excellence Mol Synth, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China
2.Jinan Univ, Sch Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat, Guangzhou 510632, Peoples R China
3.Jinan Univ, Sch Pharm, Guangzhou City Key Lab Precis Chem Drug Dev, Innovat Drug Discovery Chinese Minist Educ MOE, Guangzhou 510632, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Ajou Univ, Sch Med, Dept Surg, Suwon 16499, Gyeonggi Do, South Korea
6.Jinan Univ, Affiliated Hosp 1, Huaqiao Hosp, Guangzhou 510632, Peoples R China
推荐引用方式
GB/T 7714
Chan, Shingpan,Zhang, Yunong,Wang, Jie,et al. Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(22):15374-15390.
APA Chan, Shingpan.,Zhang, Yunong.,Wang, Jie.,Yu, Qiuchun.,Peng, Xia.,...&Ding, Ke.(2022).Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,65(22),15374-15390.
MLA Chan, Shingpan,et al."Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 65.22(2022):15374-15390.

入库方式: OAI收割

来源:上海药物研究所

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