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Download fileA Small Molecule Compound Targeting STAT3 DNA-Binding Domain Inhibits Cancer Cell Proliferation, Migration, and Invasion
journal contribution
posted on 2015-12-17, 02:10 authored by Wei Huang, Zizheng Dong, Fang Wang, Hui Peng, Jing-Yuan Liu, Jian-Ting ZhangSignal transducer and activator of
transcription 3 (STAT3) plays
important roles in multiple aspects of cancer aggressiveness including
migration, invasion, survival, self-renewal, angiogenesis, and tumor
cell immune evasion by regulating the expression of multiple downstream
target genes. STAT3 is constitutively activated in many malignant
tumors and its activation is associated with high histological grade
and advanced cancer stages. Thus, inhibiting STAT3 promises an attracting
strategy for treatment of advanced and metastatic cancers. Herein,
we identified a STAT3 inhibitor, inS3-54, by targeting the DNA-binding
domain of STAT3 using an improved virtual screening strategy. InS3-54
preferentially suppresses proliferation of cancer over non-cancer
cells and inhibits migration and invasion of malignant cells. Biochemical
analyses show that inS3-54 selectively inhibits STAT3 binding to DNA
without affecting the activation and dimerization of STAT3. Furthermore,
inS3-54 inhibits expression of STAT3 downstream target genes and STAT3
binding to chromatin in situ. Thus, inS3-54 represents a novel probe
for development of specific inhibitors targeting the DNA-binding domain
of STAT3 and a potential therapeutic for cancer treatments.