5CEQ: Dlk In Complex With Inhibitor 2-((1-cyclopentyl-5-(1-(oxetan-3-yl) Piperidin-4-yl)-1h-pyrazol-3-yl)amino)isonicotinonitrile

Citation:
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.
PDB ID: 5CEQDownload
MMDB ID: 133358
PDB Deposition Date: 2015/7/7
Updated in MMDB: 2015/11
Experimental Method:
x-ray diffraction
Resolution: 1.91  Å
Source Organism:
Similar Structures:
Biological Unit for 5CEQ: monomeric; determined by author and by software (PISA)
Molecular Components in 5CEQ
Label Count Molecule
Protein (1 molecule)
1
Mitogen-activated Protein Kinase Kinase Kinase 12(Gene symbol: MAP3K12)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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