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. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors

文献类型：期刊论文

作者Meng, Xiang-Dong1; Gao, Li-Xin1,2; Wang, Zhi-Jia1; Feng, Bo2,3; Zhang, Chun1,4; Satheeshkumar, Rajendran5; Li, Jia2; Zhu, Yun-Long6; Zhou, Yu-Bo2,3; Wang, Wen-Long1
刊名BIOORGANIC CHEMISTRY
出版日期2021-11-01
卷号116页码:13
关键词2,5-diphenyl-1,3,4-oxadiazole derivatives SHP2 Inhibitors Structure-activity relationships (SAR)
ISSN号0045-2068
DOI10.1016/j.bioorg.2021.105384
通讯作者Zhu, Yun-Long(sequoia113847@163.com) ; Zhou, Yu-Bo(ybzhou@simm.ac.cn) ; Wang, Wen-Long(wwenlong2011@163.com)
英文摘要The Src homology-2 domain containing-protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. As an oncoprotein as well as a potential immunomodulator, SHP2 has now emerged as an attractive target for novel anti-cancer agents. Although significant progress has been made in identifying chemotypes of SHP2 inhibitors, these specific compounds might not be clinically useful to inhibit frequently encountered mutated SHP2 variants. Consequently, it is highly desirable to develop chemically different SHP2 inhibitors sensitive to SHP2 mutants. This work developed a new type of SHP2 inhibitors with 2,5-diaryl-1,3,4-oxadiazole scaffold. The representative compound 6l exhibited SHP2 inhibitory activity with IC50 of 2.73 +/- 0.20 mu M, showed about 1.56-fold, 5.26-fold, and 7.36-fold selectivity for SHP2 over SHP1, PTP1B and TCPTP respectively. Further investigations confirmed that 6l behaved as mixedtype inhibitor sensitive to leukemia cell TF-1 and inhibited SHP2 mediated cell signaling and proliferation. Molecular dynamics simulation provided more detailed information on the binding modes of compounds and SHP2 protein. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors sensitive to SHP2 mutants with optimal potency and improved pharmacological properties.
WOS关键词PTPN11 ; 1B ; MUTATIONS ; PTP1B ; ACID
资助项目National Natural Science Foundation of China[21772068] ; National Natural Science Foundation of China[81773779] ; Natural Science Foundation of Jiangsu Province[BK20190608]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000705131500009
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/298466]  
专题新药研究国家重点实验室
通讯作者Zhu, Yun-Long; Zhou, Yu-Bo; Wang, Wen-Long
作者单位1.Jiangnan Univ, Sch Pharmaceut Sci, Wuxi 214122, Jiangsu, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Inst Drug Discovery & Dev, Zhongshan 528400, Peoples R China
4.Nanjing Univ, Sch Chem & Chem Engn, Nanjing 210023, Peoples R China
5.Pontificia Univ Catolica Chile, Fac Chem & Pharm, Dept Organ Chem, Santiago 702843, Chile
6.Nanjing Med Univ, Affiliated Wuxi Matern & Child Hlth Care Hosp, Wuxi 214002, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Meng, Xiang-Dong,Gao, Li-Xin,Wang, Zhi-Jia,et al. Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors[J]. BIOORGANIC CHEMISTRY,2021,116:13.
APA Meng, Xiang-Dong.,Gao, Li-Xin.,Wang, Zhi-Jia.,Feng, Bo.,Zhang, Chun.,...&Wang, Wen-Long.(2021).Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors.BIOORGANIC CHEMISTRY,116,13.
MLA Meng, Xiang-Dong,et al."Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors".BIOORGANIC CHEMISTRY 116(2021):13.

入库方式： OAI收割

来源：上海药物研究所

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。