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Discovery of 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxamide derivatives as PI3K alpha inhibitors via virtual screening and docking-based structure optimization

文献类型：期刊论文

作者Gu, Dongyan1; Zhang, Mengmeng2; Cai, Lvtao1; Wang, Chang2; Zhou, Yu -Bo2; Li, Jia2; Sheng, Rong1
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2023-05-15
卷号86页码:15
关键词PI3K alpha inhibitors Virtual screening Structure optimization
ISSN号0968-0896
DOI10.1016/j.bmc.2023.117288
通讯作者Zhou, Yu -Bo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Sheng, Rong(shengr@zju.edu.cn)
英文摘要Compound 1 with pyrazolo[1,5-a]quinoxalin-4(5H)-one scaffold was identified as a PI3K alpha inhibitor hit via virtual screening strategy. Additional similarity search and molecular docking based structural modification yielded a novel series of pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives. The most potent compound 49b exhibited remarkably improved PI3K alpha inhibitory activity with IC50 value of 0.24 mu M and moderate to good isoform selectivity over other class I PI3K isoforms. In addition, 49b significantly inhibited the proliferation of Kasumi-1 and T47D cells with IC50 value of 1.64 and 1.82 mu M, respectively. Further PK study demonstrated that it has favorable pharmacokinetic profiles (AUC(0-t) = 3294.05 ng.h/mL at 5.0 mg/kg PO, F = 91.8%). All these data indicated that compound 49b was a promising PI3Ka inhibitor with beneficial drug-like properties and merited further development.
WOS关键词DOSE-ESCALATION ; PHASE-I ; PHOSPHOINOSITIDE-3-KINASE
资助项目National Natural Science Foundation of China[8200130524]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000991826400001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/306596]  
专题新药研究国家重点实验室
通讯作者Zhou, Yu -Bo; Li, Jia; Sheng, Rong
作者单位1.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Gu, Dongyan,Zhang, Mengmeng,Cai, Lvtao,et al. Discovery of 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxamide derivatives as PI3K alpha inhibitors via virtual screening and docking-based structure optimization[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2023,86:15.
APA Gu, Dongyan.,Zhang, Mengmeng.,Cai, Lvtao.,Wang, Chang.,Zhou, Yu -Bo.,...&Sheng, Rong.(2023).Discovery of 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxamide derivatives as PI3K alpha inhibitors via virtual screening and docking-based structure optimization.BIOORGANIC & MEDICINAL CHEMISTRY,86,15.
MLA Gu, Dongyan,et al."Discovery of 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxamide derivatives as PI3K alpha inhibitors via virtual screening and docking-based structure optimization".BIOORGANIC & MEDICINAL CHEMISTRY 86(2023):15.

入库方式： OAI收割

来源：上海药物研究所

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