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

Yan Zhong1, Lin Deng1, Shuo Shi1, Qiu-yao Huang1, Shu-min Ou-Yang1, Jian-shan Mo1, Kai Zhu2, Xin-ming Qu2, Pei-qing Liu1, Yuan-xiang Wang1, Xiao-lei Zhang1
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
Correspondence to: Pei-qing Liu:, Yuan-xiang Wang:, Xiao-lei Zhang:,
DOI: 10.1038/s41401-021-00718-0
Received: 8 April 2021
Accepted: 14 June 2021
Advance online: 15 July 2021


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.
Keywords: STAT3 inhibitor; WZ-2-033; TNBC; gastric cancer

Article Options

Download Citation

Cited times in Scopus