DOI: 10.1002/ame2.12437
Targeting ASK1 by CS17919 alleviates kidney-and liver-related diseases in murine models
Guoqiang Liao1
Qianjiao Yang2
Xuhua Mao3
Yiru Zhao3
Beizhong Chen3
Kun Zhang2
Yu Zhang2
Ping Zhang3
Zhengli Chen4
Shengjian Huang5
1.Chengdu Chipscreen Pharmaceutical Corp.,Ltd.,Chengdu,Sichuan,P.R.China;Laboratory of Experimental Animal Disease Model,College of Veterinary Medicine,Sichuan Agricultural University,Chengdu,Sichuan,P.R.China2.Shenzhen Chipscreen Biosciences Co.,Ltd.,Shenzhen,Guangdong,P.R.China3.Chengdu Chipscreen Pharmaceutical Corp.,Ltd.,Chengdu,Sichuan,P.R.China4.Laboratory of Experimental Animal Disease Model,College of Veterinary Medicine,Sichuan Agricultural University,Chengdu,Sichuan,P.R.China5.Chengdu Chipscreen Pharmaceutical Corp.,Ltd.,Chengdu,Sichuan,P.R.China;Shenzhen Chipscreen Biosciences Co.,Ltd.,Shenzhen,Guangdong,P.R.China
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 THRβ agonist(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.
机标关键词：modelsalleviatesdiseaseskidney-andliver-relatedmurinetargeting
论文发表日期：2025-01-28
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：12( 102-113 )
英文信息