Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
J Med Chem. 2022 Oct 13;65(19):12650-12674. doi: 10.1021/acs.jmedchem.2c00413. Epub 2022 Sep 14.
Accumulating evidence has documented that STAT3 phosphorylation at Tyr and Ser jointly promotes the initiation and progression of gastric cancer. However, most reported STAT3 inhibitors have mainly focused on suppressing STAT3 phosphorylation at Tyr while ignoring the tumorigenic effects of phosphorylation at Ser. Herein, we described the design, synthesis, and structure-activity relationship studies on a series of triaromatic heterocyclic derivatives as potent dual phosphorylation STAT3 inhibitors. These efforts led to the discovery of the best compound () among the investigated ones, a novel, highly potent, and orally bioavailable STAT3 inhibitor possessing lower nanomolar inhibitory activity toward p-Tyr and p-Ser. Target validation revealed that selectively targets STAT3 to remarkably inhibit its canonical and noncanonical activation and corresponding biological functions, thereby resulting in the growth inhibition of gastric cancer in vitro and in vivo, highlighting the therapeutic potential of dual phosphorylation STAT3 inhibitors for gastric cancer.
越来越多的证据表明，STAT3 的 Tyr 和 Ser 位磷酸化共同促进了胃癌的发生和发展。然而，大多数报道的 STAT3 抑制剂主要集中在抑制 Tyr 位磷酸化，而忽略了 Ser 位磷酸化的致癌作用。在此，我们描述了一系列三芳杂环衍生物作为强效双重磷酸化 STAT3 抑制剂的设计、合成和构效关系研究。这些努力发现了所研究化合物中最好的化合物 ()，这是一种新型的、高效的、口服生物利用的 STAT3 抑制剂，对 p-Tyr 和 p-Ser 的抑制活性低于纳摩尔级。靶标验证表明，选择性地针对 STAT3，显著抑制其经典和非经典激活及其相应的生物学功能，从而导致体外和体内胃癌的生长抑制，突出了双重磷酸化 STAT3 抑制剂在胃癌治疗中的潜力。
