Abstract
Phosphoinositide 3-kinase (PI3K) β signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors in which PI3Kβ potency was built in a PI3Kδ-selective template. This work led to the discovery of a highly selective PI3Kβ/δ inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.
MeSH terms
-
Animals
-
Cell Line, Tumor
-
Class Ia Phosphatidylinositol 3-Kinase / metabolism
-
Dogs
-
Haplorhini
-
Humans
-
Male
-
Mice
-
Models, Molecular
-
PTEN Phosphohydrolase / genetics*
-
Phosphoinositide-3 Kinase Inhibitors*
-
Prostate / drug effects
-
Prostate / metabolism
-
Prostate / pathology
-
Prostatic Neoplasms / drug therapy*
-
Prostatic Neoplasms / genetics
-
Prostatic Neoplasms / metabolism
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacokinetics
-
Protein Kinase Inhibitors / pharmacology
-
Protein Kinase Inhibitors / therapeutic use*
-
Rats
-
Rats, Sprague-Dawley
Substances
-
Phosphoinositide-3 Kinase Inhibitors
-
Protein Kinase Inhibitors
-
Class Ia Phosphatidylinositol 3-Kinase
-
PTEN Phosphohydrolase
-
PTEN protein, human