8DEG

Crystal structure of DLK in complex with inhibitor DN0011197

8DEG の概要

• エントリーDOI: 10.2210/pdb8deg/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase 12, methyl (1S,4S)-5-{(4P)-4-[5-amino-6-(difluoromethoxy)pyrazin-2-yl]-6-[(1R,4R)-2-azabicyclo[2.1.1]hexan-2-yl]pyridin-2-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3 entities in total)
• 機能のキーワード: dlk, kinase, inhibitor, signaling protein, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36883.27

構造登録者

Srivastava, A.,Lexa, K.,de Vicente, J. (登録日: 2022-06-20, 公開日: 2022-12-14, 最終更新日: 2024-04-03)

主引用文献

Craig 2nd, R.A.,Fox, B.M.,Hu, C.,Lexa, K.W.,Osipov, M.,Thottumkara, A.P.,Larhammar, M.,Miyamoto, T.,Rana, A.,Kane, L.A.,Yulyaningsih, E.,Solanoy, H.,Nguyen, H.,Chau, R.,Earr, T.,Kajiwara, Y.,Fleck, D.,Lucas, A.,Haddick, P.C.G.,Takahashi, R.H.,Tong, V.,Wang, J.,Canet, M.J.,Poda, S.B.,Scearce-Levie, K.,Srivastava, A.,Sweeney, Z.K.,Xu, M.,Zhang, R.,He, J.,Lei, Y.,Zhuo, Z.,de Vicente, J.
Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis.
J.Med.Chem., 65:16290-16312, 2022

PubMed Abstract: Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis.

PubMed: 36469401
DOI: 10.1021/acs.jmedchem.2c01056

実験手法

X-RAY DIFFRACTION (2.79 Å)