2. Academic Validation
  3. S3I-201 derivative incorporating naphthoquinone unit as effective STAT3 inhibitors: Design, synthesis and anti-gastric cancer evaluation

S3I-201 derivative incorporating naphthoquinone unit as effective STAT3 inhibitors: Design, synthesis and anti-gastric cancer evaluation

  • Bioorg Med Chem. 2022 Oct 1:71:116941. doi: 10.1016/j.bmc.2022.116941.
Haobin Li 1,  Maohua Cai 1,  Fei Cao 2,  Dehua Yu 1,  Jing Yang 1,  Wenkai Yu 1,  Chu Chu 2,  Xiaoqing Guan 3,  Jiang-Jiang Qin 4,  Jinyun Dong 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  • 2 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China.
  • 3 Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China; Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
  • 4 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China; Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China. Electronic address: jqin@ucas.ac.cn.
  • 5 Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China; Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China. Electronic address: dongjy@ibmc.ac.cn.
PMID: 35944386 DOI: 10.1016/j.bmc.2022.116941
Abstract

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of many human cancers and has been widely recognized as a promising target for Cancer therapy. A variety of small-molecule inhibitors have been developed for targeting STAT3, and some of them are now undergoing clinical trials. S3I-201, a known STAT3 Inhibitor, may block STAT3 function in Cancer cells by binding to the STAT3 SH2 domain to disrupt STAT3 protein complex formation. Using S3I-201 as a starting point for drug development, we synthesized a series of new STAT3 inhibitors 9a-x in this study by introducing naphthoquinone unit, a privileged fragment in STAT3 inhibitors. Most of the compounds exhibited strong anti-proliferation activity of gastric Cancer cells (MGC803, MKN28, MNK1, and AGS). The representative compound 9n (SIL-14) could effectively inhibit the colony formation and migration of gastric Cancer cells MGC803, arrest the cell cycle and induce MGC803 cell Apoptosis at low micromolar concentrations in vitro. In addition, SIL-14 can also inhibit the phosphorylation of STAT3 protein and significantly decrease the expression of total STAT3, suggesting that it may exert Anticancer effects by blocking the STAT3 signaling pathway. These results support that SIL-14 may be a promising STAT3 Inhibitor for the further development of potential anti-gastric Cancer candidates.

Keywords

Anti-gastric cancer drug; Quinone derivative; S3I-201; STAT3 inhibitor.

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