title: Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors.
abstract: G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-associated coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compounds possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compound, 12n (CCG-224406), had an IC50 for GRK2 of 130 nM, >700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new inhibitors were crystallized with GRK2 to give molecular insights into the binding and kinase selectivity of this class of inhibitors.
authors.forename: Helen V
authors.initials: HV
authors.lastname: Waldschmidt
authors.forename: Kristoff T
authors.initials: KT
authors.lastname: Homan
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Cruz-Rodríguez
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Cato
authors.forename: Jessica
authors.initials: J
authors.lastname: Waninger-Saroni
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Larimore
authors.affiliation: Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cannavo
authors.affiliation: Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Song
authors.affiliation: Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kirchhoff
authors.affiliation: Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: John J G
authors.initials: JJ
authors.lastname: Tesmer
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases