5CEO

DLK in complex with inhibitor 2-((6-(3,3-difluoropyrrolidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile

5CEO の概要

• エントリーDOI: 10.2210/pdb5ceo/pdb
• 関連するPDBエントリー: 5CEN 5CEP 5CEQ
• 分子名称: Mitogen-activated protein kinase kinase kinase 12, 2-[[6-[3,3-bis(fluoranyl)pyrrolidin-1-yl]-4-[1-(oxetan-3-yl)piperidin-4-yl]pyridin-2-yl]amino]pyridine-4-carbonitrile (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: 34458.52

構造登録者

HARRIS, S.F.,YIN, J. (登録日: 2015-07-07, 公開日: 2015-10-14, 最終更新日: 2024-03-06)

主引用文献

Patel, S.,Harris, S.F.,Gibbons, P.,Deshmukh, G.,Gustafson, A.,Kellar, T.,Lin, H.,Liu, X.,Liu, Y.,Liu, Y.,Ma, C.,Scearce-Levie, K.,Ghosh, A.S.,Shin, Y.G.,Solanoy, H.,Wang, J.,Wang, B.,Yin, J.,Siu, M.,Lewcock, J.W.
Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12).
J.Med.Chem., 58:8182-8199, 2015

PubMed Abstract: Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.

PubMed: 26431428
DOI: 10.1021/acs.jmedchem.5b01072

実験手法

X-RAY DIFFRACTION (2.28 Å)