title: Identification of small molecule inhibitors of proline-rich tyrosine kinase 2 (Pyk2) with osteogenic activity in osteoblast cells.
abstract: A screening campaign of a diverse collection of approximately 250,000 small molecule compounds was performed to identify inhibitors of proline-rich tyrosine kinase 2 (Pyk2) with potential osteogenic activity in osteoblast cells. Compounds were prioritized based on selectivity following a counter-screen against focal adhesion kinase (FAK), a closely related kinase. 4-Amino and 5-aryl substituted pyridinone series were identified that showed strong biochemical potency against Pyk2 and up to 3700-fold selectivity over FAK. Modeling analysis suggested that structural differences in the substrate binding cleft could explain the high selectivity of these chemical series against FAK. Representative compounds from each series showed inhibition of Pyk2 autophosphorylation in 293T cells (IC(50) approximately 0.11 microM), complete inhibition of endogenous Pyk2 in A7r5 cells and increased levels of osteogenic markers in MC3T3 osteoblast cells (EC(50)'s approximately 0.01 microM). These results revealed a new class of compounds with osteogenic-inducing activity in osteoblast cells and a starting point for the development of more potent and selective Pyk2 inhibitors.
authors: Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors: John G
authors: JG
authors: Allen
authors: Matthew R
authors: MR
authors: Lee
authors: Chun-Ya E
authors: CY
authors: Han
authors: Jon
authors: J
authors: Scherrer
authors: Shaun
authors: S
authors: Flynn
authors: Christy
authors: C
authors: Boucher
authors: Huilin
authors: H
authors: Zhao
authors: Anne B
authors: AB
authors: O'Connor
authors: Philip
authors: P
authors: Roveto
authors: David
authors: D
authors: Bauer
authors: Russell
authors: R
authors: Graceffa
authors: William G
authors: WG
authors: Richards
authors: Philip
authors: P
authors: Babij
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D054852:Small Molecule Libraries; D051418:Focal Adhesion Kinase 2