title: Identification of type-II inhibitors using kinase structures.
abstract: Spleen tyrosine kinase is a non-receptor tyrosine kinase, overactivation 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 spleen tyrosine kinase. 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 spleen tyrosine kinase Type-II ligands. Compounds 1 and 3 were found to bind to the DFG-out conformation of spleen tyrosine kinase, 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.
authors: World Wide Medicinal Chemistry, Pfizer Worldwide R & D, 200 Cambridgepark Drive, Cambridge, MA 02140, USA. frank.lovering@pfizer.com
authors: Frank
authors: F
authors: Lovering
authors: Joseph
authors: J
authors: McDonald
authors: Gavin A
authors: GA
authors: Whitlock
authors: Paul A
authors: PA
authors: Glossop
authors: Chris
authors: C
authors: Phillips
authors: Andrew
authors: A
authors: Bent
authors: Yogesh
authors: Y
authors: Sabnis
authors: Mark
authors: M
authors: Ryan
authors: Lori
authors: L
authors: Fitz
authors: Julie
authors: J
authors: Lee
authors: Jeanne S
authors: JS
authors: Chang
authors: Seungil
authors: S
authors: Han
authors: Ravi
authors: R
authors: Kurumbail
authors: Atli
authors: A
authors: Thorarensen
mesh_terms: D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013154:Spleen / Q000201:enzymology; D000072377:Syk Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase