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 |
DOI | 10.1021/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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