Small-molecule compounds targeting the STAT3 DNA-binding domain suppress survival of cisplatin-resistant human ovarian cancer cells by inducing apoptosis

Wei Huang, Yuan Liu, Jun Wang, Xia Yuan, Hong Wei Jin, Liang Ren Zhang, Jian Ting Zhang, Zhen Ming Liu, Jing Rong Cui

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) plays important roles in oncogenic occurrence and transformation by regulating the expression of diverse downstream target genes important for tumor growth, metastasis, angiogenesis and immune evasion. Feasibility of targeting the DNA-binding domain (DBD) of STAT3 has been proven previously. With the aid of 3D shape- and electrostatic-based drug design, we identified a new STAT3 inhibitor, LC28, and its five analogs, based on the pharmacophore of a known STAT3 DBD inhibitor. Microscale thermophoresis assay shows that these compounds inhibits STAT3 binding to DNA with a Ki value of 0.74–8.87 μM. Furthermore, LC28 and its analogs suppress survival of cisplatin-resistant ovarian cancer cells by inhibiting STAT3 signaling and inducing apoptosis. Therefore, these compounds may serve as candidate compounds for further modification and development as anticancer therapeutics targeting the DBD of human STAT3 for treatment of cisplatin-resistant ovarian cancer.

Original languageEnglish (US)
Pages (from-to)887-897
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume157
DOIs
StatePublished - Sep 5 2018

Keywords

  • Cisplatin resistance
  • DNA binding domain (DBD)
  • Microscale thermophoresis
  • Signal transducer and activator of transcription 3 (STAT3)
  • Similarity screening

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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