6BBU

Crystal Structure of JAK1 in complex with compound 25

6BBU の概要

• エントリーDOI: 10.2210/pdb6bbu/pdb
• 関連するPDBエントリー: 6BBV
• 分子名称: Tyrosine-protein kinase JAK1, N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (3 entities in total)
• 機能のキーワード: kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endomembrane system; Peripheral membrane protein: P23458
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36740.88

構造登録者

Han, S. (登録日: 2017-10-19, 公開日: 2018-01-17, 最終更新日: 2024-10-16)

主引用文献

Vazquez, M.L.,Kaila, N.,Strohbach, J.W.,Trzupek, J.D.,Brown, M.F.,Flanagan, M.E.,Mitton-Fry, M.J.,Johnson, T.A.,TenBrink, R.E.,Arnold, E.P.,Basak, A.,Heasley, S.E.,Kwon, S.,Langille, J.,Parikh, M.D.,Griffin, S.H.,Casavant, J.M.,Duclos, B.A.,Fenwick, A.E.,Harris, T.M.,Han, S.,Caspers, N.,Dowty, M.E.,Yang, X.,Banker, M.E.,Hegen, M.,Symanowicz, P.T.,Li, L.,Wang, L.,Lin, T.H.,Jussif, J.,Clark, J.D.,Telliez, J.B.,Robinson, R.P.,Unwalla, R.
Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.
J. Med. Chem., 61:1130-1152, 2018

PubMed Abstract: Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.

PubMed: 29298069
DOI: 10.1021/acs.jmedchem.7b01598

実験手法

X-RAY DIFFRACTION (2.08 Å)