title: Discovery of potent and selective rhodanine type IKKβ inhibitors by hit-to-lead strategy.
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.
authors.affiliation: Department of Chemistry, Korea University, Seongbuk-gu, Seoul 136-713, Republic of Korea.
authors.forename: Hyeseung
authors.initials: H
authors.lastname: Song
authors.forename: Yun Suk
authors.initials: YS
authors.lastname: Lee
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Roh
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
authors.forename: Kwang-Seok
authors.initials: KS
authors.lastname: Oh
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Hogyu
authors.initials: H
authors.lastname: Han
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology; D012236:Rhodanine / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D012236:Rhodanine; D051550:I-kappa B Kinase