5VO1

DLK in complex with compound 10 (5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine)

5VO1 の概要

• エントリーDOI: 10.2210/pdb5vo1/pdb
• 関連するPDBエントリー: 5VO1
• 分子名称: Mitogen-activated protein kinase kinase kinase 12, 5-{5-[(1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-(propan-2-yl)-1H-pyrazol-3-yl}-3-(trifluoromethyl)pyridin-2-amine (3 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q12852
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34425.46

構造登録者

HARRIS, S.F.,YIN, J. (登録日: 2017-05-01, 公開日: 2017-10-04, 最終更新日: 2023-10-04)

主引用文献

Patel, S.,Meilandt, W.J.,Erickson, R.I.,Chen, J.,Deshmukh, G.,Estrada, A.A.,Fuji, R.N.,Gibbons, P.,Gustafson, A.,Harris, S.F.,Imperio, J.,Liu, W.,Liu, X.,Liu, Y.,Lyssikatos, J.P.,Ma, C.,Yin, J.,Lewcock, J.W.,Siu, M.
Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease.
J. Med. Chem., 60:8083-8102, 2017

PubMed Abstract: Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain.

PubMed: 28929759
DOI: 10.1021/acs.jmedchem.7b00843

実験手法

X-RAY DIFFRACTION (2.45 Å)