Discovery of 2-Amino-3-cyanothiophene Derivatives as PotentSTAT3 Inhibitors for the Treatment of Osteosarcoma Growth and Metastasis

Authors：Jin, Wangrui; Zhang, Tao; Zhou, Wenbo; He, Peng; Sun, Yue; Hu, Shijia; Chen, Huang; Ma, Xinglong; Peng, Yangrui; Yi, Zhengfang; Liu, Mingyao; Chen, Yihua^*

Source：Journal of Medicinal Chemistry, 2022, 65(9): 6710-6728.

DOI：10.1021/acs.jmedchem.2c00004

• SMALL-MOLECULE INHIBITOR
• TRANSCRIPTION FACTOR STAT3
• TUMOR-GROWTH
• DRUG DESIGN
• INVASION
• BREAST
• CELLS
• IL-6
• ACTIVATION
• EPIDEMIOLOGY

Osteosarcoma is one of the most common malignantbone tumors. However, the treatment and clinical outcomes ofosteosarcoma have hardly changed over the past three decades due tothe comprehensive heterogeneity and higher rate of mutation ofosteosarcoma. Recent studies have shown that STAT3 has the potentialto suppress the proliferation and metastasis of osteosarcoma. In thisstudy, a novel class of 2-amino-3-cyanothiophene derivatives weredesigned and synthesized to inhibit osteosarcoma by targeting STAT3.Representative compound6fshowed potent antiproliferative effectsagainst osteosarcoma cells, directly bound to the STAT3 SH2 domainwith aKDof 0.46 mu M, and inhibited the phosphorylation of STAT3Y705 in a dose-dependent manner. Furthermore, compound6fpromoted osteosarcoma cell apoptosisin vitroand significantly suppressed the growth and metastasis of osteosarcomain vivo.Thesefindings demonstrate that targeting STAT3 may be a feasible therapeutic strategy for the treatment of metastatic osteosarcoma

• Institution
  上海交通大学