Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one Scaffold.
Serhii A LiakhovIgor A SchepetkinOlexander S KarpenkoHanna I DumaNadiia M HaidarzhyLiliya N KirpotinaAnastasia R KovrizhinaAndrei I KhlebnikovIrina Y BagryanskayaMark T QuinnPublished in: Molecules (Basel, Switzerland) (2021)
c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury. Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We synthesized 13 derivatives of our reported JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human MonoMac-6 cells, respectively. Selected compounds (4f and 4m) also inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs.
Keyphrases
- induced apoptosis
- signaling pathway
- lps induced
- endoplasmic reticulum stress
- oxidative stress
- inflammatory response
- cell cycle arrest
- pi k akt
- cell death
- small molecule
- nuclear factor
- rheumatoid arthritis
- ischemia reperfusion injury
- endothelial cells
- epithelial mesenchymal transition
- toll like receptor
- single molecule
- risk assessment
- immune response
- climate change
- tyrosine kinase