3H3C

Crystal structure of PYK2 in complex with Sulfoximine-substituted trifluoromethylpyrimidine analog

3H3C の概要

• エントリーDOI: 10.2210/pdb3h3c/pdb
• 分子名称: Protein tyrosine kinase 2 beta, SULFATE ION, 4-{[4-{[(1R,2R)-2-(dimethylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: pyk2, kinase, alternative splicing, atp-binding, cell membrane, cytoplasm, membrane, nucleotide-binding, phosphoprotein, polymorphism, transferase, tyrosine-protein kinase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q14289
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33129.14

構造登録者

Han, S.,Mistry, A. (登録日: 2009-04-16, 公開日: 2009-05-26, 最終更新日: 2024-02-21)

主引用文献

Walker, D.P.,Zawistoski, M.P.,McGlynn, M.A.,Li, J.C.,Kung, D.W.,Bonnette, P.C.,Baumann, A.,Buckbinder, L.,Houser, J.A.,Boer, J.,Mistry, A.,Han, S.,Xing, L.,Guzman-Perez, A.
Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity.
Bioorg.Med.Chem.Lett., 19:3253-3258, 2009

PubMed Abstract: The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model.

PubMed: 19428251
DOI: 10.1016/j.bmcl.2009.04.093

実験手法

X-RAY DIFFRACTION (2 Å)