3VF8: Crystal Structure of Spleen Tyrosine Kinase Syk Catalytic Domain with Pyrazolylbenzimidazole Inhibitor 416

Beginning with a screening hit, unique thienopyrazole-indole inhibitors of Itk (interleukin-2-inducible tyrosine kinase) were designed, synthesized, and crystallized in the target kinase. Although initial compounds were highly active in Itk, they were not selective. Increasing the steric bulk around a tertiary alcohol at the 5-indole position dramatically improved selectivity toward Lyk and Syk, but not Txk. Substitutions at the 3- and 4-indole positions gave less active compounds that remained poorly selective. A difluoromethyl substitution at the 5-position of the thienopyrazole led to a highly potent and selective compound. Phenyl at this position reduced activity and selectivity while pushing the side-chains of Lys-391 and Asp-500 away from the binding pocket. Novel and selective thienopyrazole inhibitors of Itk were designed as a result of combining structure-based design and medicinal chemistry.
PDB ID: 3VF8Download
MMDB ID: 99200
PDB Deposition Date: 2012/1/9
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.08  Å
Source Organism:
Similar Structures:
Biological Unit for 3VF8: monomeric; determined by author and by software (PISA)
Molecular Components in 3VF8
Label Count Molecule
Protein (1 molecule)
Tyrosine-protein Kinase SYK(Gene symbol: SYK)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB