8TB5

TYK2 JH2 bound to Compound7

8TB5 の概要

• エントリーDOI: 10.2210/pdb8tb5/pdb
• 分子名称: Non-receptor tyrosine-protein kinase TYK2, ACETATE ION, N-{(3P)-3-[3-(dimethylsulfamoyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-5-yl}cyclopropanecarboxamide, ... (4 entities in total)
• 機能のキーワード: tyk2, pseudokinase, azaindole, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 73873.59

構造登録者

Argiriadi, M.A.,Van Epps, S.A.,Breinlinger, E.C. (登録日: 2023-06-28, 公開日: 2023-10-18, 最終更新日: 2023-11-08)

主引用文献

Breinlinger, E.,Van Epps, S.,Friedman, M.,Argiriadi, M.,Chien, E.,Chhor, G.,Cowart, M.,Dunstan, T.,Graff, C.,Hardee, D.,Herold, J.M.,Little, A.,McCarthy, R.,Parmentier, J.,Perham, M.,Qiu, W.,Schrimpf, M.,Vargo, T.,Webster, M.P.,Wu, F.,Bennett, D.,Edmunds, J.
Targeting the Tyrosine Kinase 2 (TYK2) Pseudokinase Domain: Discovery of the Selective TYK2 Inhibitor ABBV-712.
J.Med.Chem., 66:14335-14356, 2023

PubMed Abstract: Tyrosine kinase 2 (TYK2) is a nonreceptor tyrosine kinase that belongs to the JAK family also comprising JAK1, JAK2, and JAK3. TYK2 is an attractive target for various autoimmune diseases as it regulates signal transduction downstream of IL-23 and IL-12 receptors. Selective TYK2 inhibition offers a differentiated clinical profile compared to currently approved JAK inhibitors. However, selectivity for TYK2 versus other JAK family members has been difficult to achieve with small molecules that inhibit the catalytically active kinase domain. Successful targeting of the TYK2 pseudokinase domain as a strategy to achieve isoform selectivity was recently exemplified with deucravacitinib. Described herein is the optimization of selective TYK2 inhibitors targeting the pseudokinase domain, resulting in the discovery of the clinical candidate ABBV-712 ().

PubMed: 37823891
DOI: 10.1021/acs.jmedchem.3c01373

実験手法

X-RAY DIFFRACTION (2.32 Å)