Targeting ASK1 by CS17919 alleviates kidney-and liver-related diseases in murine models  

作　　者：Guoqiang Liao Qianjiao Yang Xuhua Mao Yiru Zhao Beizhong Chen Kun Zhang Yu Zhang Ping Zhang Zhengli Chen Shengjian Huang 

机构地区：[1]Chengdu Chipscreen Pharmaceutical Corp.,Ltd.,Chengdu,Sichuan,P.R.China [2]Laboratory of Experimental Animal Disease Model,College of Veterinary Medicine,Sichuan Agricultural University,Chengdu,Sichuan,P.R.China [3]Shenzhen Chipscreen Biosciences Co.,Ltd.,Shenzhen,Guangdong,P.R.China

出　　处：《Animal Models and Experimental Medicine》2025年第1期102-113,共12页动物模型与实验医学(英文)

摘　　要：Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhibition of ASK1 kinase ac-tivity can protect cells from pathological injury.In this study,we designed and synthe-sized a novel selective ASK1 inhibitor,CS17919,and investigated its pharmacological effects in various animal models of metabolic injury.Methods:First,we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib(GS-4997),a phase III ASK1 inhibitor.We then conducted pharmacokinetic(PK)studies in mice.Finally,we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease(CKD)and non-alcoholic steatohepatitis(NASH).Results:Compared to GS-4997,CS17919 demonstrated comparable inhibition of ASK1 in vitro,exhibited lower toxicity,and provided greater protection in palmitic acid-treated LO2 cells.CS17919 also showed pronounced pharmacokinetic prop-erties such as a high plasma concentration.In the unilateral ureteral obstruction model(UUO),CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis.In the diabetic kidney disease(DKD)model,CS17919 significantly improved serum creatinine and glomerular sclerosis.In the NASH model,the combination of CS17919 and a THRβagonist(CS27109)was found to significantly improve liver inflammation and substantially reduced liver fibrosis.Conclusions:CS17919 showed cell protective,anti-inflammatory,and antifibrotic ef-fects in vitro and in vivo,suggesting its therapeutic potential for metabolic-related kidney and liver diseases.

关 键 词：ASK1_(1) CKD_(4) CS17919_(2) GS-4997_(3) NASH_(5) 

分 类 号：X70[环境科学与工程—环境工程]