Structure-based optimization of potent PDK1 inhibitors.
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.
Angiolini
Mauro
M
Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy. mauro.angiolini@nervianoms.com
Banfi
Patrizia
P
Casale
Elena
E
Casuscelli
Francesco
F
Fiorelli
Claudio
C
Saccardo
Maria B
MB
Silvagni
Marco
M
Zuccotto
Fabio
F
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*
D047428:Protein Kinase Inhibitors; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases