Pyridazinone derivatives have been extensively used as anticancer agents. IMB5036 is a structure specific pyridazinone compound with potential antitumor activity via targeting KSRP protein which controls gene expression at multiple levels. In this study, fifteen IMB5036 analogues were synthesized and preliminary structure-activity relationships were explored. Among them, compounds and exhibited remarkably anti-proliferation of various cancer cells and a good cancer cell selectivity (against human fetal hepatocyte L02 cells). More detailed investigation was included that both and inhibited colony formation and migration in concentration-dependent mode against MCF-7 cells. Additionally, and induced apoptosis and cell cycle arrest, decreased mitochondrial membrane potential, damaged DNA, and increased reactive oxygen species. Moreover, displayed a potent antitumor efficacy (TGI = 74.2 %, at a dose of 30 mg/kg) in MCF-7 xenograft model by i.p. injection. Further, we synthesized a biotinylated probe for identifying the detail domain of KSRP. Through pull down assay and molecular docking study, we validated that the KH23 domain functioned as the binding pocket for the compounds. Thus, compound was identified as a novel targeting KSRP pyridazinone-based compound and exhibited excellent antitumor activity both and .

中文翻译：

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新型哒嗪酮衍生物与 KSRP 结合：合成、抗肿瘤生物学评价和建模见解


哒嗪酮衍生物已广泛用作抗癌剂。 IMB5036 是一种结构特异性哒嗪酮化合物，通过靶向控制多个水平基因表达的 KSRP 蛋白，具有潜在的抗肿瘤活性。在本研究中，合成了 15 种 IMB5036 类似物，并探索了初步的构效关系。其中，化合物和化合物对多种癌细胞表现出显着的抗增殖作用，并具有良好的癌细胞选择性（针对人胎肝细胞L02细胞）。更详细的研究表明， 和 均以浓度依赖性模式抑制 MCF-7 细胞的集落形成和迁移。此外，还诱导细胞凋亡和细胞周期停滞、线粒体膜电位降低、DNA 损伤和活性氧增加。此外，通过腹腔注射在 MCF-7 异种移植模型中显示出有效的抗肿瘤功效（TGI = 74.2%，剂量为 30 mg/kg）。此外，我们合成了一种生物素化探针，用于识别 KSRP 的详细结构域。通过pull down实验和分子对接研究，我们验证了KH23结构域作为化合物的结合口袋的功能。因此，该化合物被鉴定为新型靶向KSRP哒嗪酮类化合物，并表现出优异的抗肿瘤活性。