5CEN: Crystal Structure Of Dlk (kinase Domain)

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.
PDB ID: 5CENDownload
MMDB ID: 133355
PDB Deposition Date: 2015/7/7
Updated in MMDB: 2015/11
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 5CEN: monomeric; determined by author and by software (PISA)
Molecular Components in 5CEN
Label Count Molecule
Protein (1 molecule)
Mitogen-activated Protein Kinase Kinase Kinase 12(Gene symbol: MAP3K12)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB