5VO2

DLK in complex with inhibitor 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine (compound 7)

Summary for 5VO2

• Entry DOI: 10.2210/pdb5vo2/pdb
• Related: 5VO1
• Descriptor: Mitogen-activated protein kinase kinase kinase 12, 5-{5-[1-(oxetan-3-yl)piperidin-4-yl]-1-(propan-2-yl)-1H-pyrazol-3-yl}-3-(trifluoromethyl)pyridin-2-amine (3 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q12852
• Total number of polymer chains: 1
• Total formula weight: 34427.48

Authors

HARRIS, S.F.,YIN, J. (deposition date: 2017-05-01, release date: 2017-10-04, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.96 Å)