Abstract：
Apoptosis signal regulated kinase 1 (ASK1, MAP3K5) is a member of the mitogen activated protein kinase (MAPK) signaling pathway, involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has become a promising strategy for the treatment of Non-alcoholic steatohepatitis (NASH) disease. A series of novel ASK1 inhibitors with indazole scaffolds were designed and synthesized, and their ASK1 kinase activities were evaluated. The System Structure Activity Relationship (SAR) study discovered a promising compound 33c, which has a strong inhibitory effect on ASK1. Noteworthy observations included a discernible reduction in lipid droplets within LO2 cells stained with Oil Red O, coupled with a decrease in LDL, CHO, and TG content within the NASH model cell group. Mechanistic inquiries revealed that compound 33c could inhibit the protein expression levels of the upregulated ASK1-p38/JNK signaling pathway in TNF-α treated HGC-27 cells and regulate apoptotic proteins. In summary, these findings suggest that compound 33c may be valuable for further research as a potential candidate compound against NASH.
摘要：
凋亡信号调节激酶1(ASK1,MAP3K5)是丝裂原活化蛋白激酶(MAPK)信号通路中的一员,参与细胞存活，分化,应激反应，和凋亡。ASK1激酶抑制已成为治疗非酒精性脂肪性肝炎（NASH）疾病的有希望的策略。设计并合成了一系列新型的以吲哚为支架的ASK1抑制剂,并对其ASK1激酶活性进行了评价。系统构效关系(SAR)研究发现了一种有前景的化合物33c,对ASK1有很强的抑制作用。值得注意的观察结果包括油红O染色的LO2细胞内脂滴的明显减少，再加上低密度脂蛋白的减少，CHO,和NASH模型细胞组内的TG含量。机制研究表明，化合物33c可以抑制TNF-α处理的HGC-27细胞中上调的ASK1-p38/JNK信号通路的蛋白表达水平，并调节凋亡蛋白。总之,这些发现提示,化合物33c作为抗NASH的潜在候选化合物可能对进一步研究有价值.
