Abstract
Regulation of NF-κB activation through the inhibition of IKKβ has been identified as a promising target for the treatment of inflammatory and autoimmune disease such as rheumatoid arthritis. In order to develop novel IKKβ inhibitors, we performed high throughput screening toward around 8000 library compounds, and identified a hit compound containing rhodanine moiety. We modified the structure of hit compound to obtain potent and selective IKKβ inhibitors. Throughout hit-to-lead studies, we have discovered optimized compounds which possess blocking effect toward NF-κB activation and TNFα production in cell as well as inhibition activity against IKKβ. Among them, compound 3q showed the potent inhibitory activity against IKKβ, and excellent selectivity over other kinases such as p38α, p38β, JNK1, JNK2, and JNK3 as well as IKKα.
| Original language | English |
|---|---|
| Pages (from-to) | 5668-5674 |
| Number of pages | 7 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 22 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - 2012 Sept 1 |
Bibliographical note
Funding Information:This work was financially supported by Research Fund 2011 of The Catholic University of Korea and Development of Bio-oriented Technology Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology.
Keywords
- Hit-to-lead
- IKKβ inhibitor
- NF-κB
- Reumatoid athritis
- TNFα
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry