Rapid access to unexplored chemical space by ligand scanning around a ruthenium center: discovery of potent and selective protein kinase inhibitors.
An important objective for the discovery of compounds with unique biological activities is the development of methods for the synthesis of molecular scaffolds with defined three-dimensional shapes. We are currently investigating the scope of using metal complexes to accomplish this goal. In these compounds, the metal center has the role of organizing the orientation of the organic ligands, thus defining the overall shape of the molecule. A strategy is presented that allows a rapid scanning of ligands around a ruthenium center in the search for ligand spheres that are complementary in shape and functional group presentation to ATP binding sites of protein kinases. Following this approach, we have identified octahedral ruthenium complexes as potent inhibitors for the protein kinases Pim1, MSK1, and GSK3alpha.
Bregman
Howard
H
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, USA.
Carroll
Patrick J
PJ
Meggers
Eric
E
D002227:Carbazoles / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D005656:Fungal Proteins; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D007700:Kinetics; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors; D012428:Ruthenium / Q000737:chemistry*; D019311:Staurosporine / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D002227:Carbazoles; D005656:Fungal Proteins; D008024:Ligands; D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D012428:Ruthenium; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D020928:Mitogen-Activated Protein Kinases; C432694:Pim1 protein, Pichia pastoris; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D019311:Staurosporine