6X8E

Crystal structure of JAK2 with Compound 11

6X8E の概要

• エントリーDOI: 10.2210/pdb6x8e/pdb
• 分子名称: Tyrosine-protein kinase JAK2, [3-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1H-pyrazol-1-yl}-1-(2,2,2-trifluoroethyl)azetidin-3-yl]acetonitrile (3 entities in total)
• 機能のキーワード: kinase, transferase
• 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: 70950.19

構造登録者

Vajdos, F.F.,Knafels, J.D. (登録日: 2020-06-01, 公開日: 2020-11-25, 最終更新日: 2024-10-16)

主引用文献

Gerstenberger, B.S.,Ambler, C.,Arnold, E.P.,Banker, M.E.,Brown, M.F.,Clark, J.D.,Dermenci, A.,Dowty, M.E.,Fensome, A.,Fish, S.,Hayward, M.M.,Hegen, M.,Hollingshead, B.D.,Knafels, J.D.,Lin, D.W.,Lin, T.H.,Owen, D.R.,Saiah, E.,Sharma, R.,Vajdos, F.F.,Xing, L.,Yang, X.,Yang, X.,Wright, S.W.
Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases.
J.Med.Chem., 63:13561-13577, 2020

PubMed Abstract: Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 ().

PubMed: 32787094
DOI: 10.1021/acs.jmedchem.0c00948

実験手法

X-RAY DIFFRACTION (1.75 Å)