He Peng, Bian Aiwu, Miao Ying, Jin Wangrui, Chen Huang, He Jia, Li Liting, Sun Yue, Ye Jiangnan, Liu Mingyao, Yi Zhengfang, Zhou Wenbo, Chen Yihua
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai200241, China.
Shanghai Yuyao Biotech Co., Ltd., Shanghai200241, China.
J Med Chem. 2022 Nov 24;65(22):15487-15511. doi: 10.1021/acs.jmedchem.2c01554. Epub 2022 Oct 25.
Increasing evidence has demonstrated that STAT3 phosphorylation at Tyr and Ser is closely associated with the progression and poor prognosis of pancreatic cancer. Herein, we report the function-based screening, SAR studies, and biological activity evaluation of a series of novel STAT3 dual phosphorylation inhibitors with an indole-containing tetra-aromatic heterocycle scaffold. Our efforts led to the discovery of optimal compound among the investigated ones, showing desirable ADME properties and highly potent antitumor activities and . By targeting the STAT3 SH2 domain, significantly blocked p-Tyr and p-Ser and caused the abrogation of the corresponding nuclear transcription and mitochondrial oxidative phosphorylation functions of STAT3 in the low nanomolar range. Except for nanomolar antiproliferation activities , oral treatment of exhibited significant suppressive effects and tolerance in a pancreatic cancer xenograft model, indicating that could be useful for pancreatic cancer treatment as a STAT3 dual phosphorylation inhibitor.
越来越多的证据表明，信号转导与转录激活因子3（STAT3）在酪氨酸（Tyr）和丝氨酸（Ser）位点的磷酸化与胰腺癌的进展及不良预后密切相关。在此，我们报告了一系列具有含吲哚四芳杂环支架的新型STAT3双重磷酸化抑制剂的基于功能的筛选、构效关系（SAR）研究及生物活性评估。我们的研究工作导致在所研究的化合物中发现了最优化合物，其显示出理想的药代动力学性质及高效的抗肿瘤活性。通过靶向STAT3的Src同源2（SH2）结构域，该化合物在低纳摩尔范围内显著阻断酪氨酸磷酸化（p-Tyr）和丝氨酸磷酸化（p-Ser），并导致STAT3相应的核转录和线粒体氧化磷酸化功能丧失。除了具有纳摩尔级的抗增殖活性外，该化合物的口服给药在胰腺癌异种移植模型中表现出显著的抑制作用和耐受性，表明该化合物作为STAT3双重磷酸化抑制剂可用于胰腺癌治疗。
