6NZQ

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound_29 AKA 6-[(5-FLUORO-4-METH YLPYRIDIN-2-YL)AMINO]-4-({2-METHOXY-3-[(PYRIDIN-2-YLMETHYL )CARBAMOYL]PHENYL}AMINO)-N-METHYLPYRIDINE-3-CARBOXAMIDE

6NZQ の概要

• エントリーDOI: 10.2210/pdb6nzq/pdb
• 分子名称: Non-receptor tyrosine-protein kinase TYK2, 6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-[(2-methoxy-3-{[(pyridin-2-yl)methyl]carbamoyl}phenyl)amino]-N-methylpyridine-3-carboxamide (3 entities in total)
• 機能のキーワード: jtk1, pseudokinase, 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: 72029.39

構造登録者

Khan, J.A. (登録日: 2019-02-14, 公開日: 2019-07-31, 最終更新日: 2023-10-11)

主引用文献

Wrobleski, S.T.,Moslin, R.,Lin, S.,Zhang, Y.,Spergel, S.,Kempson, J.,Tokarski, J.S.,Strnad, J.,Zupa-Fernandez, A.,Cheng, L.,Shuster, D.,Gillooly, K.,Yang, X.,Heimrich, E.,McIntyre, K.W.,Chaudhry, C.,Khan, J.,Ruzanov, M.,Tredup, J.,Mulligan, D.,Xie, D.,Sun, H.,Huang, C.,D'Arienzo, C.,Aranibar, N.,Chiney, M.,Chimalakonda, A.,Pitts, W.J.,Lombardo, L.,Carter, P.H.,Burke, J.R.,Weinstein, D.S.
Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165.
J.Med.Chem., 62:8973-8995, 2019

PubMed Abstract: Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 () as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

PubMed: 31318208
DOI: 10.1021/acs.jmedchem.9b00444

実験手法

X-RAY DIFFRACTION (2.11 Å)