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.

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;Innovation Practice Center,Changchun University of Chinese Medicine,Changchun 130117,China

[1]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-.The novel STAT3 inhibitor WZ-2-033 causes regression of human triple-negative breast cancer and gastric cancer xenografts)[J].中国药理学报（英文版）,2022(04):1013-1023

Hyperactive,pY705

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