title: Discovery of Tyk2 inhibitors via the virtual site-directed fragment-based drug design.
abstract: In this study, we synthesized compound 12 with potent Tyk2 inhibitory activity from FBDD study and carried out a cell-based assay for Tyk2/STAT3 signaling activation upon IFNα5 stimulation. Compound 12 completely suppressed the IFNα5-mediated Tyk2/STAT3 signaling pathway as well as the basal levels of pSTAT3. Stimulation with IFNα/β leads to the tyrosine phosphorylation of the JAK1 and Tyk2 receptor-associated kinases with subsequent STATs activation, transmitting signals from the cell surface receptor to the nucleus. In conclusion, the potency of compound 12 to interrupt the signal transmission of Tyk2/STAT3 appeared to be equivalent or superior to that of the reference compound.
authors.affiliation: Graduate School of New Drug Discovery and Development, Chungnam National University, Daehakno 99, Yuseong-gu, Daejeon 305-764, Republic of Korea.
authors.forename: Woo Dae
authors.initials: WD
authors.lastname: Jang
authors.affiliation: Graduate School of New Drug Discovery and Development, Chungnam National University, Daehakno 99, Yuseong-gu, Daejeon 305-764, Republic of Korea.
authors.forename: Jun-Tae
authors.initials: JT
authors.lastname: Kim
authors.affiliation: Research Center for Medicinal Chemistry, Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors.forename: Hoon Young
authors.initials: HY
authors.lastname: Son
authors.affiliation: College of Pharmacy, Keimyung University, 1000 Sindang-dong, Dalseo-Gu, Daegu, Republic of Korea.
authors.forename: Seung Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: College of Pharmacy, Keimyung University, 1000 Sindang-dong, Dalseo-Gu, Daegu, Republic of Korea.
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Graduate School of New Drug Discovery and Development, Chungnam National University, Daehakno 99, Yuseong-gu, Daejeon 305-764, Republic of Korea.
authors.forename: Tae-sung
authors.initials: TS
authors.lastname: Koo
authors.affiliation: Research Center for Medicinal Chemistry, Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-600, Republic of Korea. Electronic address: leeh@krict.re.kr.
authors.forename: Hyuk
authors.initials: H
authors.lastname: Lee
authors.affiliation: Graduate School of New Drug Discovery and Development, Chungnam National University, Daehakno 99, Yuseong-gu, Daejeon 305-764, Republic of Korea. Electronic address: nskang@cnu.ac.kr.
authors.forename: Nam Sook
authors.initials: NS
authors.lastname: Kang
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D053634:TYK2 Kinase; C070139:TYK2 protein, human
keywords: FBDD; Inhibitor; STATs activation; Tyk2; Water-ring analysis