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Discovery of pyrido[4,3-d]pyrimidinone derivatives as novel Wee1 inhibitors

文献类型：期刊论文

作者Ye, Qingqing2; Ma, Jingkun3,4; Wang, Peipei1; Wang, Chang3; Sun, Mei2; Zhou, Yubo3,4; Li, Jia1,3,4; Liu, Tao2
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2023-05-03
卷号87页码:12
ISSN号0968-0896
关键词Wee1 inhibitor Scaffold hopping
DOI10.1016/j.bmc.2023.117312
通讯作者Zhou, Yubo(ybzhou@mail.shcnc.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Liu, Tao(lt601@zju.edu.cn)
英文摘要Wee1 has emerged as a potential target in cancer therapy due to its critical role in the regulation of the cell cycle. Here, we describe a series of Wee1 inhibitors with a novel scaffold that are potent inhibitors of this kinase (IC50 = 19-1485 nM). These inhibitors demonstrated robust cytotoxicity in MV-4-11 and T47D cell lines (MV-4-11 IC50 = 660-2690 nM, T47D IC50 = 2670-20,000 nM) and displayed good stability in mouse liver microsomes in vitro. Additionally, compound 34 showed remarkable selectivity (more than 500-fold) over the other 9 kinases. Further mechanistic studies demonstrated that compound 34 displayed measurable effects on downstream biomarkers and induced cancer cell apoptosis and cell cycle arrest in the G0/G1 phase. Taken together, these results show that compound 34, potentially a leading Wee1 inhibitor, warrants further investigation.
WOS关键词KINASE ; CELLS
资助项目High-level new RD Institute[2019B090904008] ; High-level Innovative Research Institute of the Department of Science and Technology of Guangdong Province[2021B0909050003]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
出版者PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号WOS:001009786300001
源URL[http://119.78.100.183/handle/2S10ELR8/306191]  
专题新药研究国家重点实验室
通讯作者Zhou, Yubo; Li, Jia; Liu, Tao
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
推荐引用方式
GB/T 7714		 Ye, Qingqing,Ma, Jingkun,Wang, Peipei,et al. Discovery of pyrido[4,3-d]pyrimidinone derivatives as novel Wee1 inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2023,87:12.
APA Ye, Qingqing.,Ma, Jingkun.,Wang, Peipei.,Wang, Chang.,Sun, Mei.,...&Liu, Tao.(2023).Discovery of pyrido[4,3-d]pyrimidinone derivatives as novel Wee1 inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,87,12.
MLA Ye, Qingqing,et al."Discovery of pyrido[4,3-d]pyrimidinone derivatives as novel Wee1 inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 87(2023):12.

入库方式： OAI收割

来源：上海药物研究所

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