5CEN

Crystal structure of DLK (kinase domain)

Summary for 5CEN

• Entry DOI: 10.2210/pdb5cen/pdb
• Related: 5CEO 5CEP 5CEQ
• Descriptor: Mitogen-activated protein kinase kinase kinase 12 (2 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q12852
• Total number of polymer chains: 1
• Total formula weight: 34018.03

Authors

HARRIS, S.F.,YIN, J. (deposition date: 2015-07-07, release date: 2015-10-14, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.7 Å)