@article{1cb9b7f55e264e7c99eb2345edfa198b,
title = "Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer",
abstract = "Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.",
keywords = "Anticancer, Ca signaling, Drug discovery, Nonselective cation channels, TRPC channels",
author = "Mingmin Ding and Hongbo Wang and Chunrong Qu and Fuchun Xu and Yingmin Zhu and Guangyao Lv and Yungang Lu and Qingjun Zhou and Hui Zhou and Xiaodong Zeng and Jingwen Zhang and Chunhong Yan and Jiacheng Lin and Luo, {Huai Rong} and Zixing Deng and Yuling Xiao and Jinbin Tian and Zhu, {Michael X.} and Xuechuan Hong",
note = "Funding Information: This work was partially supported by NSFC (81773674, 81728020, 81573383, 21390402), US National Institutes of Health (NS056942, NS092377), the Applied Basic Research Programs of Scientific and Technologic Council of Suzhou (SYG201521), Key Research Project of Shandong Province (2017GSF18177), Natural Science Foundation of Jiangsu Province (BK20160387), Natural Science Foundation of Hubei Province (2017CFA024, 2017CFB711, 2016ACA126), Shenzhen Science and Technology Research Grant (JCYJ20170303170809222), Natural Science Foundation of the Tibet Autonomous Region (2016ZR-15-9), Foundation for University Young Teacher of Tibet Autonomous Region (QCZ2016-10), the Fundamental Research Funds for the Central Universities and the Open Research Fund Program of the Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals. Funding Information: This work was partially supported by NSFC ( 81773674 , 81728020 , 81573383 , 21390402 ), US National Institutes of Health ( NS056942 , NS092377 ), the Applied Basic Research Programs of Scientific and Technologic Council of Suzhou ( SYG201521 ), Key Research Project of Shandong Province ( 2017GSF18177 ), Natural Science Foundation of Jiangsu Province ( BK20160387 ), Natural Science Foundation of Hubei Province ( 2017CFA024 , 2017CFB711 , 2016ACA126 ), Shenzhen Science and Technology Research Grant ( JCYJ20170303170809222 ), Natural Science Foundation of the Tibet Autonomous Region ( 2016ZR-15-9 ), Foundation for University Young Teacher of Tibet Autonomous Region ( QCZ2016-10 ), the Fundamental Research Funds for the Central Universities and the Open Research Fund Program of the Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals . Publisher Copyright: {\textcopyright} 2018 Elsevier B.V.",
year = "2018",
month = sep,
day = "28",
doi = "10.1016/j.canlet.2018.05.041",
language = "English (US)",
volume = "432",
pages = "47--55",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
}