Discovery of potent and selective rhodanine type IKKβ inhibitors by hit-to-lead strategy

Title
Discovery of potent and selective rhodanine type IKKβ inhibitors by hit-to-lead strategy
Authors
송혜승이윤석노은주서재홍오광석이병호Hogyu Han신계정
Keywords
IKKβ inhibitor; allosteric inhibitor; anti-inflammation; NF-κB; TNFα; Hit-to-lead
Issue Date
2012-09
Publisher
Bioorganic & medicinal chemistry letters
Citation
VOL 22, NO 17, 5668-5674
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.
URI
http://pubs.kist.re.kr/handle/201004/44309
ISSN
0960894X
Appears in Collections:
KIST Publication > Article
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