新型STAT3抑制剂的设计、合成与优化及其抗胰腺癌活性研究

Pancreatic cancer is a malignant tumor of the digestive tract with a high degree of malignancy and is difficult to diagnose and treat. There is no targeted drug for pancreatic cancer. The genes that are widely mutated in pancreatic cancer are K-RAS (>90%) and TP53 (74-86%), but these two genes are currently considered to be un-targetable. Recent literature and clinical progresses show that targeted STAT3 can be used for the treatment of K-RAS and TP53 mutated pancreatic cancer, while the activity of current STAT3 inhibitors remains at the sub-micromole level, so the development of a novel potent STAT3 inhibitor to treat pancreatic cancer has the dual meaning of basic research and clinical application..In the early stage of this project, a novel class of 2-amino-3-cyanothiophene derivatives was discovered to inhibit pancreatic cancer by targeting STAT3. More than 100 compounds were synthesized by structural modification and optimization. The representative compound WB-436B showed direct binding to the SH2 domain of STAT3 through three experiments of SPR, MST and ITC, and its activity was better than the clinical STAT3 inhibitor BP-1-102 and C188-9. WB-436B can selectively inhibit the proliferation and induce apoptosis of pancreatic cancer cells with high expression of p-STAT3Tyr705, and can also inhibit the growth of mouse pancreatic tumors in vivo. This project will continue to improve the activity of STAT3 inhibitors, taking into account the drug-forming properties of the compounds, laying the foundation for the clinical development of this type of STAT3 inhibitor.

胰腺癌是致死率最高的恶性肿瘤之一，目前还没有靶向药物上市。通过靶向STAT3用于治疗K-RAS和TP53突变的胰腺癌受到了广泛关注，已成为抗肿瘤药物研发的热门领域之一。而目前已发表STAT3抑制剂活性还停留在微摩尔级别，因此开发高效STAT3抑制剂用来治疗胰腺癌具有基础研究和临床应用的双重意义。本项目前期通过基于结构的药物设计发现了一类新型2-氨基-3-氰基噻吩衍生物的STAT3抑制剂，代表性化合物WB-436B和STAT3的亲和力为104nM，优于现有STAT3抑制剂C188-9和BP-1-102。细胞实验表明WB-436B能够选择性抑制p-STAT3高表达胰腺癌的增殖，体内结果也显示WB-436B通过靶向STAT3抑制小鼠胰腺肿瘤的生长。本项目将以上结果为基础继续提高STAT3抑制剂的活性，兼顾化合物的选择性和成药性，为该类型STAT3抑制剂的临床奠定基础。

胰腺癌是致死率最高的恶性肿瘤之一，目前还没有靶向药物上市。通过靶向STAT3用于治疗K-RAS和TP53突变的胰腺癌受到了广泛关注，已成为抗肿瘤药物研发的热门领域之一。而目前已发表STAT3抑制剂活性还停留在微摩尔级别，因此开发高效STAT3抑制剂用来治疗胰腺癌具有基础研究和临床应用的双重意义。本项目前期通过基于结构的药物设计发现了一类新型2-氨基-3-氰基噻吩衍生物的STAT3抑制剂，代表性化合物WB-436B和STAT3的亲和力为94nM，优于现有STAT3抑制剂C188-9和BP-1-102。细胞实验表明WB-436B能够选择性抑制p-STAT3高表达胰腺癌的增殖，体内结果也显示WB-436B通过靶向STAT3抑制小鼠胰腺肿瘤的生长。本项目提高了STAT3抑制剂的活性，兼顾化合物的选择性和成药性，为该类型STAT3抑制剂的临床奠定基础。

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