3VF9

Crystal Structure of Spleen Tyrosine Kinase Syk Catalytic Domain with Thienopyrazolylindole Inhibitor 027

Summary for 3VF9

• Entry DOI: 10.2210/pdb3vf9/pdb
• Related: 3V5J 3V5L 3V8T 3V8W 3VF8
• Descriptor: Tyrosine-protein kinase SYK, 3-{2-[5-(difluoromethyl)-2H-thieno[3,2-c]pyrazol-3-yl]-1H-indol-6-yl}pentan-3-ol (3 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane : P43405
• Total number of polymer chains: 1
• Total formula weight: 35256.40

Authors

McLean, L.R.,Zhang, Y. (deposition date: 2012-01-09, release date: 2012-05-02, Last modification date: 2024-02-28)

Primary citation

McLean, L.R.,Zhang, Y.,Zaidi, N.,Bi, X.,Wang, R.,Dharanipragada, R.,Jurcak, J.G.,Gillespy, T.A.,Zhao, Z.,Musick, K.Y.,Choi, Y.M.,Barrague, M.,Peppard, J.,Smicker, M.,Duguid, M.,Parkar, A.,Fordham, J.,Kominos, D.
X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase.
Bioorg.Med.Chem.Lett., 22:3296-3300, 2012

PubMed Abstract: 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.

PubMed: 22464456
DOI: 10.1016/j.bmcl.2012.03.016

Experimental method

X-RAY DIFFRACTION (2.3 Å)