4W8E

Structure of MST3 with a pyrrolopyrimidine inhibitor (PF-06645342)

4W8E の概要

• エントリーDOI: 10.2210/pdb4w8e/pdb
• 関連するPDBエントリー: 4W8D
• 分子名称: Serine/threonine-protein kinase 24 36 kDa subunit, 3-{4-[(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile (3 entities in total)
• 機能のキーワード: mst3, pyrrolopyrimidine, kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q9Y6E0
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33429.25

構造登録者

Jasti, J.,Song, X.,Griffor, M.,Kurumbail, R.G. (登録日: 2014-08-24, 公開日: 2015-03-18, 最終更新日: 2023-12-27)

主引用文献

Henderson, J.L.,Kormos, B.L.,Hayward, M.M.,Coffman, K.J.,Jasti, J.,Kurumbail, R.G.,Wager, T.T.,Verhoest, P.R.,Noell, G.S.,Chen, Y.,Needle, E.,Berger, Z.,Steyn, S.J.,Houle, C.,Hirst, W.D.,Galatsis, P.
Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor.
J.Med.Chem., 58:419-432, 2015

PubMed Abstract: Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.

PubMed: 25353650
DOI: 10.1021/jm5014055

実験手法

X-RAY DIFFRACTION (1.79 Å)