3tub

Publication Abstract from PubMed

Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase, over-activation of which is thought to contribute to autoimmune diseases as well as allergy and asthma. Protein kinases have a highly conserved ATP binding site, thus making challenging the design of selective small molecule inhibitors. It has been well documented that some protein kinases can be stabilized in their inactive conformations (Type-II inhibitors). Herein we describe a protein structure / ligand based approach to successfully identify ligands that bind to novel conformations of Syk. By utilizing kinase protein crystal structures both in the public domain (RCSB) and within Pfizer's protein crystal database we report the discovery of the first Syk Type-II ligands. Compounds 1 and 3 were found to bind to the DFG-out conformation of Syk while compound 2 binds to a DFG-in, C-Helix out conformation. In this instance the C-helix moved significantly to create a large hydrophobic pocket rarely seen in kinase protein crystal structures. (c) 2012 Pfizer Inc.

Identification of Type-II Inhibitors Using Kinase Structures.,Lovering F, McDonald J, Whitlock GA, Glossop PA, Phillips C, Bent A, Sabnis Y, Ryan M, Fitz L, Lee J, Chang JS, Han S, Kurumbail R, Thorarensen A Chem Biol Drug Des. 2012 Jul 3. doi: 10.1111/j.1747-0285.2012.01443.x. PMID:22759374^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.