Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) family, is implicated in many human diseases. Here, we describe the structural optimization of hit compound 7 and conduct further structure-activity relationship (SAR) studies that result in the development of compound 19 with a novel indole-2-carboxamide hinge scaffold. Compound 19 displays potent anti-ASK1 kinase activity and stronger inhibitory effect on ASK1 in AP1-HEK293 cells than previously described ASK1 inhibitor GS-4997. Besides improved in vitro activity, compound 19 also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 19 shows significant anti-UC efficacy and markedly attenuates DSS-induced body weight loss, colonic shortening, elevation in disease activity index (DAI) and inflammatory cell infiltration in colon tissues. Mechanistically, compound 19 represses the phosphorylation of ASK1-p38/JNK signaling pathways and suppresses the overexpression of inflammatory cytokines. Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.ejmech.2020.113114 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
GS-4997 halts the progression of tubulointerstitial injury in lupus nephritis.
FASEB J
December 2024
Department of Nephrology, Hunan Clinical Research Center for Chronic Kidney Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People's Republic of China.
Tubulointerstitial injury has been increasingly recognized as an important component in lupus nephritis (LN) pathology over the last decades. However, current clinical treatment options for this process remain limited. In this study, we aimed to investigate the potential benefits of GS-4997, a selective inhibitor of ASK1, in tubulointerstitial injury of LN.
View Article and Find Full Text PDFArticle Synopsis
- * The study focuses on the activation of Apoptosis signal-regulating kinase 1 (ASK-1) in advanced DKD using an ASK-1 inhibitor (GS442172), demonstrating that inhibiting ASK-1 can reduce kidney injury and improve conditions like albuminuria.
- * Findings suggest that ASK-1 activation leads to cellular senescence and glomerular damage through redox signaling, indicating that targeting ASK-1 could be a promising therapeutic approach for treating DKD.
Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors.
J Enzyme Inhib Med Chem
December 2024
Jiangxi Provincial Key Laboratory of TCM Female Reproductive Health and Related Diseases Research and Transformation, Jiangxi University of Chinese Medicine, Nanchang, PR China.
Inhibiting apoptosis signal regulated kinase 1 (ASK1) is an attractive strategy for treating diseases such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we report the discovery of a dibromo substituted quinoxaline fragment containing as an effective small-molecule inhibitor of ASK1, with an IC value of 30.17 nM.
View Article and Find Full Text PDFEndothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α.
Am J Physiol Lung Cell Mol Physiol
October 2024
Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States.
In hypoxic and pseudohypoxic rodent models of pulmonary hypertension (PH), hypoxia-inducible factor (HIF) inhibition attenuates disease initiation. However, HIF activation alone, due to genetic alterations or use of inhibitors of prolyl hydroxylase domain (PHD) enzymes, has not been definitively shown to cause PH in humans, indicating the involvement of other mechanisms. Given the association between endothelial cell dysfunction and PH, the effects of pseudohypoxia and its underlying pathways were investigated in primary human lung endothelial cells.
View Article and Find Full Text PDFTherapeutic potential of ASK1 activators in cancer treatment: Current insights and future directions.
Biomed Pharmacother
September 2024
State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China. Electronic address:
Apoptosis signal-regulated kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase (MAP3K) family, whose activation and regulation are intricately associated with apoptosis. ASK1 is activated in response to oxidative stress, among other stimuli, subsequently triggering downstream JNK, p38 MAPK, and mitochondria-dependent apoptotic signaling, which participate in the initiation of tumor cell apoptosis induced by various stimuli. Research has shown that ASK1 plays a crucial role in the apoptosis of lung cancer, breast cancer, and liver cancer cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!