The novel STAT3 inhibitor WZ-2-033 causes regression of human triple-negative breast cancer and gastric cancer xenografts  

作　　者：Yan Zhong Lin Deng Shuo Shi Qiu-yao Huang Shu-min Ou-Yang Jian-shan Mo Kai Zhu Xin-ming Qu Pei-qing Liu Yuan-xiang Wang Xiao-lei Zhang 

机构地区：[1]National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation,Guangdong Engineering Laboratory of Druggability and New Drug Evaluation,Guangdong Key Laboratory of Chiral Molecule and Drug Discovery,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou,510006,China [2]Innovation Practice Center,Changchun University of Chinese Medicine,Changchun,130117,China

出　　处：《Acta Pharmacologica Sinica》2022年第4期1013-1023,共11页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(81973359 and 21977128);Guangdong Basic and Applied Basic Research Foundation(2019A1515011215);Guangzhou Basic and Applied Basic Research Foundation(202002030408 and 202103000097);Grants from the Fundamental Research Funds for the Central Universities,Sun Yat-sen University(2021qntd44);Jilin Province Science and Technology Development Project(20190304046YY and 20200404105YY);National Engineering and Technology Research Center for New Drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004);National Major Special Projects for the Creation and Manufacture of New Drugs(2019ZX09301104);Key-Area Research and Development Program of Guangdong Province(2020B1111110003);Guangdong Provincial Key Laboratory of Construction Foundation(2019B030301005)are also appreciated.

摘　　要：Hyperactive signal transducer and activator of transcription 3 (STAT3) signaling is frequently detected in human triple-negative breast cancer (TNBC) and gastric cancer, leading to uncontrolled tumor growth, resistance to chemotherapy, and poor prognosis. Thus, inhibition of STAT3 signaling is a promising therapeutic approach for both TNBC and gastric cancer, which have high incidences and mortality and limited effective therapeutic approaches. Here, we report a small molecule, WZ-2-033, capable of inhibiting STAT3 activation and dimerization and STAT3-related malignant transformation. We present in vitro evidence from surface plasmon resonance analysis that WZ-2-033 interacts with the STAT3 protein and from confocal imaging that WZ-2-033 disrupts HA-STAT3 and Flag-STAT3 dimerization in intact cells. WZ-2-033 suppresses STAT3-DNA-binding activity but has no effect on STAT5-DNA binding. WZ-2-033 inhibits the phosphorylation and nuclear accumulation of pY705-STAT3 and consequently suppresses STAT3-dependent transcriptional activity and the expression of STAT3 downstream genes. Moreover, WZ-2-033 significantly inhibited the proliferation, colony survival, migration, and invasion of TNBC cells and gastric cancer cells with aberrant STAT3 activation. Furthermore, administration of WZ-2-033 in vivo induced a significant antitumor response in mouse models of TNBC and gastric cancer that correlated with the inhibition of constitutively active STAT3 and the suppression of known STAT3 downstream genes. Thus, our study provides a novel STAT3 inhibitor with significant antitumor activity in human TNBC and gastric cancer harboring persistently active STAT3.

关 键 词：STAT3 inhibitor WZ-2-033 TNBC gastric canc 

分 类 号：R73[医药卫生—肿瘤]