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

• Published in: European journal of medicinal chemistry 2020-09, Vol.201, p.112428-112428, Article 112428
• Main Authors: Feng, Kai-Rui, Wang, Feng, Shi, Xin-Wei, Tan, Yun-Xuan, Zhao, Jia-Ying, Zhang, Jian-Wei, Li, Qing-Hua, Lin, Guo-Qiang, Gao, Dingding, Tian, Ping
• Format: Article
• Language: English
• Subjects: Animals; Anti-tumor activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; BBI608; Benzofurans - chemical synthesis; Benzofurans - metabolism; Benzofurans - therapeutic use; Cell Line, Tumor; Drug Design; Female; Humans; Mice, Inbred BALB C; Molecular docking; Molecular Docking Simulation; Molecular Structure; Naphthoquinones - chemical synthesis; Naphthoquinones - metabolism; Naphthoquinones - therapeutic use; Neoplasms - drug therapy; Protein Binding; S Phase Cell Cycle Checkpoints - drug effects; STAT3 inhibitors; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112428

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. [Display omitted] •Novel scaffold and high potency of A11 as selective STAT3 inhibitor was discovered using structure-based design.•A11 could inhibit the activation of STAT3 (Y705) and reduced the expression of downstream gene CyclinD1 and C-Myc.•A11 suppress the MDA-MB-231 xenograft tumor growth in mice (10 mg/kg, i.p.) without obvious body weight loss.•Molecular docking study elucidated the binding mode of A11 in STAT3 SH2 domain.