Jin Wangrui, Zhang Tao, Zhou Wenbo, He Peng, Sun Yue, Hu Shijia, Chen Huang, Ma Xinglong, Peng Yangrui, Yi Zhengfang, Liu Mingyao, Chen Yihua
Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
J Med Chem. 2022 May 12;65(9):6710-6728. doi: 10.1021/acs.jmedchem.2c00004. Epub 2022 Apr 27.
Osteosarcoma is one of the most common malignant bone tumors. However, the treatment and clinical outcomes of osteosarcoma have hardly changed over the past three decades due to the comprehensive heterogeneity and higher rate of mutation of osteosarcoma. Recent studies have shown that STAT3 has the potential to suppress the proliferation and metastasis of osteosarcoma. In this study, a novel class of 2-amino-3-cyanothiophene derivatives were designed and synthesized to inhibit osteosarcoma by targeting STAT3. Representative compound showed potent antiproliferative effects against osteosarcoma cells, directly bound to the STAT3 SH2 domain with a of 0.46 μM, and inhibited the phosphorylation of STAT3 Y705 in a dose-dependent manner. Furthermore, compound promoted osteosarcoma cell apoptosis and significantly suppressed the growth and metastasis of osteosarcoma . These findings demonstrate that targeting STAT3 may be a feasible therapeutic strategy for the treatment of metastatic osteosarcoma.
骨肉瘤是最常见的恶性骨肿瘤之一。然而，由于骨肉瘤具有全面的异质性和较高的突变率，在过去三十年中，骨肉瘤的治疗方法和临床结果几乎没有改变。最近的研究表明，信号转导和转录激活因子3（STAT3）具有抑制骨肉瘤增殖和转移的潜力。在本研究中，设计并合成了一类新型的2-氨基-3-氰基噻吩衍生物，通过靶向STAT3来抑制骨肉瘤。代表性化合物对骨肉瘤细胞显示出强大的抗增殖作用，以0.46 μM的解离常数直接与STAT3的Src同源2（SH2）结构域结合，并以剂量依赖性方式抑制STAT3 Y705位点的磷酸化。此外，该化合物促进骨肉瘤细胞凋亡，并显著抑制骨肉瘤的生长和转移。这些发现表明，靶向STAT3可能是治疗转移性骨肉瘤的一种可行的治疗策略。
