中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 合肥物质科学研究院
  3. 中国科学院合肥物质科学研究院
Discovery of Pyrazolo[1,5-a]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors

文献类型：期刊论文

作者Wang, Chun2,3; Zou, Fengming1,2,4; Qi, Ziping1,2,4; Liu, Qingwang1,2,4; Shen, Lijuan2,3; Yuan, Xinyu2,3; Deng, Maoqing2,3; Wang, Aoli1,2,4; Wang, Beilei1,2,4; Wang, Li1,2,4,5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-08-20
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00817
通讯作者Liang, Xiaofei(xiaofeiliang@hmfl.ac.cn) ; Liu, Qingsong(qsliu97@hmfl.ac.cn) ; Liu, Jing(jingliu@hmfl.ac.cn)
英文摘要PI3K gamma and PI3K delta plays critical roles in exerting immunosuppression by targeting regulatory T cells and myeloid cells. Dual inhibition of PI3K gamma and PI3K delta has emerged as a novel therapeutic strategy for cancer immunotherapy. We herein report a series of pyrazolopyridine derivatives with distinct scaffolds as potent and selective dual inhibitors of PI3K gamma and PI3K delta. Among them, 20e (IHMT-PI3K-315) displays an IC50 value of 4.0 and 9.1 nM against PI3K gamma and PI3K delta respectively in biochemical assays. Meanwhile, it potently inhibits PI3K gamma and PI3K delta-mediated phosphorylation of AKT S473 with EC50 values of 0.028 and 0.013 mu M in cellular assays. In addition, 20e exhibits a favorable selectivity profile in protein kinases at 1 mu M. In bone marrow-derived macrophages (BMDM), 20e can repolarize the M2 phenotype to the M1 phenotype. In vivo, 20e demonstrates acceptable pharmacokinetic properties and suppresses tumor growth in a MC38 syngeneic mouse model.
WOS关键词INFLAMMATION ; PREDICTION ; CLEARANCE ; DISEASE ; MODELS
资助项目National Natural Science Foundation of China[82173671] ; National Natural Science Foundation of China[82373723] ; National Natural Science Foundation of China[81872745] ; National Natural Science Foundation of China[82373715] ; Major Science and Technology Project of Anhui Province[202303a07020007] ; Key Research and Development Program of Anhui Province[2023s07020018] ; CASHIPS Director's Fund[BJPY2022A02] ; Youth Innovation Promotion Association of CAS[Y202088]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001295135100001
出版者AMER CHEMICAL SOC
资助机构National Natural Science Foundation of China ; Major Science and Technology Project of Anhui Province ; Key Research and Development Program of Anhui Province ; CASHIPS Director's Fund ; Youth Innovation Promotion Association of CAS
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/136028]  
专题中国科学院合肥物质科学研究院
通讯作者Liang, Xiaofei; Liu, Qingsong; Liu, Jing
作者单位1.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Anhui, Peoples R China
2.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Hlth & Med Technol, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Anhui, Peoples R China
3.Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China
4.Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China
5.Primary Cell Engn Joint Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Chun,Zou, Fengming,Qi, Ziping,et al. Discovery of Pyrazolo[1,5-a]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024.
APA Wang, Chun.,Zou, Fengming.,Qi, Ziping.,Liu, Qingwang.,Shen, Lijuan.,...&Liu, Jing.(2024).Discovery of Pyrazolo[1,5-a]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY.
MLA Wang, Chun,et al."Discovery of Pyrazolo[1,5-a]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY (2024).

入库方式： OAI收割

来源：合肥物质科学研究院

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。