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Design, synthesis and biological evaluation of novel potent STAT3 inhibitors based on BBI608 for cancer therapy.
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-06-25 , 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 1 , Guo-Qiang Lin 3 , Dingding Gao 1 , Ping Tian 3
Affiliation  

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.



中文翻译:

基于BBI608的新型有效STAT3抑制剂的设计,合成和生物学评估。

持久激活的信号转导子和转录激活子3(STAT3)在多种癌症的发生中起着重要作用,因此是预防癌症的潜在治疗靶点。在这里,我们报告基于BBI608的新型有效STAT3抑制剂的合理设计,合成和生物学评估。其中,化合物A11对MDA-MB-231,MDA-MB-468和HepG2细胞表现出最有效的体外肿瘤细胞生长抑制活性,IC 50值低至0.67±0.02μM,0.77±0.01μM和1.24±分别为0.16μM。荧光偏振(FP)分析验证了STAT3 SH2域中化合物A11与IC 50的结合值为5.18μM。进一步的机理研究表明,A11抑制了STAT3(Y705)的激活,从而降低了STAT3下游基因CyclinD1和C-Myc的表达。同时,它以浓度依赖性方式诱导癌细胞S期停滞和凋亡。另一项体内研究表明,A11以10 mg / kg(ip)的剂量抑制了小鼠MDA-MB-231异种移植瘤的生长,而没有明显的体重减轻。最后,分子对接研究进一步阐明了STAT3 SH2结构域中A11的结合方式。

更新日期:2020-06-27
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