7UYV

Crystal structure of JAK3 kinase domain in complex with compound 25

7UYV の概要

• エントリーDOI: 10.2210/pdb7uyv/pdb
• 分子名称: Tyrosine-protein kinase JAK3, 6-{[(2M)-2-(2-chloro-6-fluorophenyl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-4-yl]amino}-N-ethylpyridine-3-carboxamide, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: non-receptor tyrosine-protein kinase jak3, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 134834.25

構造登録者

Toms, A.V.,Leit, S.,Greenwood, J.R.,Mondal, S.,Carriero, S.,Dahlgren, M.,Harriman, G.C.,Kennedy-Smith, J.J.,Kapeller, R.,Lawson, J.P.,Romero, D.L.,Shelley, M.,Wester, R.T.,Westlin, W.,Mc Elwee, J.J.,Miao, W.,Edmondson, S.D.,Massee, C.E. (登録日: 2022-05-07, 公開日: 2022-08-24)

主引用文献

Leit, S.,Greenwood, J.R.,Mondal, S.,Carriero, S.,Dahlgren, M.,Harriman, G.C.,Kennedy-Smith, J.J.,Kapeller, R.,Lawson, J.P.,Romero, D.L.,Toms, A.V.,Shelley, M.,Wester, R.T.,Westlin, W.,McElwee, J.J.,Miao, W.,Edmondson, S.D.,Masse, C.E.
Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis.
Bioorg.Med.Chem.Lett., 73:128891-128891, 2022

PubMed Abstract: TYK2 is a member of the JAK family of kinases and a key mediator of IL-12, IL-23, and type I interferon signaling. These cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genetic association studies, TYK2 inhibition is an attractive therapeutic strategy for these diseases. Herein, we report the discovery of a series of highly selective catalytic site TYK2 inhibitors designed using FEP+ and structurally enabled design starting from a virtual screen hit. We highlight the structure-based optimization to identify a lead candidate 30, a potent cellular TYK2 inhibitor with excellent selectivity, pharmacokinetic properties, and in vivo efficacy in a mouse psoriasis model.

PubMed: 35842205
DOI: 10.1016/j.bmcl.2022.128891

実験手法

X-RAY DIFFRACTION (2.15 Å)