Discovery of potent and selective rhodanine type IKK? inhibitors by hit-to-lead strategy.

Discovery of potent and selective rhodanine type IKK? inhibitors by hit-to-lead strategy.

Bioorg Med Chem Lett. 2012 Jul 15;

Authors: Song H, Lee YS, Roh EJ, Seo JH, Oh KS, Lee BH, Han H, Shin KJ

Abstract
Regulation of NF-?B activation through the inhibition of IKK? has been identified as a promising target for the treatment of inflammatory and autoimmune disease such as rheumatoid arthritis. In order to develop novel IKK? 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 IKK? inhibitors. Throughout hit-to-lead studies, we have discovered optimized compounds which possess blocking effect toward NF-?B activation and TNF? production in cell as well as inhibition activity against IKK?. Among them, compound 3q showed the potent inhibitory activity against IKK?, and excellent selectivity over other kinases such as p38?, p38?, JNK1, JNK2, and JNK3 as well as IKK?.

PMID: 22858099 [PubMed - as supplied by publisher]

kinase inhibitor library for screening compound library screening small molecule library