title: Structure-based optimization of potent PDK1 inhibitors.
abstract: In this Letter is described the structure-based design of potent dihydro-pyrazoloquinazolines as PDK1 inhibitors. Starting from low potency HTS hits with the aid of X-ray crystallography and modeling, a medicinal chemistry activity was carried out to improve potency versus PDK1 and selectivity versus CDK2 protein kinase.
authors.affiliation: Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy. mauro.angiolini@nervianoms.com
authors.forename: Mauro
authors.initials: M
authors.lastname: Angiolini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Banfi
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.forename: Francesco
authors.initials: F
authors.lastname: Casuscelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiorelli
authors.forename: Maria B
authors.initials: MB
authors.lastname: Saccardo
authors.forename: Marco
authors.initials: M
authors.lastname: Silvagni
authors.forename: Fabio
authors.initials: F
authors.lastname: Zuccotto
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases