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

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

  • Eur J Med Chem. 2018 Sep 5:157:887-897. doi: 10.1016/j.ejmech.2018.08.037.
Wei Huang 1,  Yuan Liu 2,  Jun Wang 3,  Xia Yuan 2,  Hong-Wei Jin 2,  Liang-Ren Zhang 2,  Jian-Ting Zhang 4,  Zhen-Ming Liu 5,  Jing-Rong Cui 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
  • 3 Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China.
  • 4 Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, United States.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: zmliu@bjmu.edu.cn.
PMID: 30145375 DOI: 10.1016/j.ejmech.2018.08.037
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.

Keywords

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

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