2. Academic Validation
  3. Design, synthesis and biological evaluation of novel potent STAT3 inhibitors based on BBI608 for cancer therapy

Design, synthesis and biological evaluation of novel potent STAT3 inhibitors based on BBI608 for cancer therapy

  • Eur J Med Chem. 2020 Sep 1;201:112428. doi: 10.1016/j.ejmech.2020.112428.
Kai-Rui Feng 1,  Feng Wang 1,  Xin-Wei Shi 1,  Yun-Xuan Tan 2,  Jia-Ying Zhao 1,  Jian-Wei Zhang 1,  Qing-Hua Li 3,  Guo-Qiang Lin 4,  Dingding Gao 5,  Ping Tian 6
Affiliations

Affiliations

  • 1 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 2 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
  • 3 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: qinghuali@shutcm.edu.cn.
  • 4 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
  • 5 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: gaodingding@shutcm.edu.cn.
  • 6 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China. Electronic address: tianping@shutcm.edu.cn.
PMID: 32603980 DOI: 10.1016/j.ejmech.2020.112428
Abstract

Persistently activated signal transducer and activator of transcription 3 (STAT3) plays an important role in the development of multiple cancers, and therefore is a potential therapeutic target for Cancer prevention. Herein, we report the rational design, synthesis, and biological evaluation of novel potent STAT3 inhibitors based on BBI608. Among them, compound A11 exhibited the most potent in vitro tumor cell growth inhibitory activities toward MDA-MB-231, MDA-MB-468 and HepG2 cells with IC50 values as low as 0.67 ± 0.02 μM, 0.77 ± 0.01 μM and 1.24 ± 0.16 μM, respectively. Fluorescence polarization (FP) assay validated the binding of compound A11 in STAT3 SH2 domain with the IC50 value of 5.18 μM. Further mechanistic studies indicated that A11 inhibited the activation of STAT3 (Y705), and thus reduced the expression of STAT3 downstream genes CyclinD1 and c-Myc. Simultaneously, it induced Cancer cell S phase arrest and Apoptosis in a concentration-dependent manner. An additional in vivo study revealed that A11 suppressed the MDA-MB-231 xenograft tumor growth in mice at the dose of 10 mg/kg (i.p.) without obvious body-weight loss. Finally, molecular docking study further elucidated the binding mode of A11 in STAT3 SH2 domain.

Keywords

Anti-tumor activity; BBI608; Molecular docking; STAT3 inhibitors.

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