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A small molecule compound targeting STAT3 DNA-binding domain inhibits cancer cell proliferation, migration, and

Wei Huang1, Zizheng Dong, Fang Wang

  • 1Department of Pharmacology and Toxicology and ‡IU Simon Cancer Center, Indiana University School of Medicine , 980 W. Walnut Street, Indianapolis, Indiana 46202, United States.

ACS Chemical Biology
|March 26, 2014
PubMed

Insights

We discovered inS3-54, a novel Signal transducer and activator of transcription 3 (STAT3) inhibitor. This compound selectively blocks STAT3

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is crucial in cancer progression, influencing migration, invasion, survival, angiogenesis, and immune evasion.
  • Constitutive STAT3 activation correlates with tumor grade and advanced stages, making it a promising therapeutic target for metastatic cancers.

Purpose of the Study:

  • To identify a novel inhibitor targeting the DNA-binding domain of STAT3.
  • To evaluate the efficacy of the identified inhibitor, inS3-54, in preclinical cancer models.

Main Methods:

  • Utilized an improved virtual screening strategy to identify STAT3 inhibitors.
  • Conducted biochemical analyses to assess inS3-54's mechanism of action, including STAT3 DNA binding, activation, and dimerization.
  • Evaluated inS3-54's effect on STAT3 downstream gene expression and chromatin binding in situ.

Main Results:

  • Identified inS3-54, a novel STAT3 inhibitor targeting its DNA-binding domain.
  • inS3-54 selectively suppressed cancer cell proliferation, migration, and invasion.
  • inS3-54 inhibited STAT3's DNA binding activity without affecting its activation or dimerization, and reduced downstream gene expression.

Conclusions:

  • inS3-54 is a selective inhibitor of STAT3 DNA binding, representing a novel chemical probe.
  • inS3-54 demonstrates potential as a therapeutic agent for advanced and metastatic cancers by targeting STAT3.

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