Abstract
We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
3-Phosphoinositide-Dependent Protein Kinases
-
Animals
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use
-
Binding Sites
-
Cell Line, Tumor
-
Computer Simulation
-
Drug Evaluation, Preclinical
-
Enzyme Activation / drug effects
-
Humans
-
Mice
-
Neoplasms / drug therapy
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoinositide-3 Kinase Inhibitors*
-
Phosphorylation
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacology
-
Protein Kinase Inhibitors / therapeutic use
-
Protein Serine-Threonine Kinases / antagonists & inhibitors
-
Protein Serine-Threonine Kinases / metabolism
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
-
Proto-Oncogene Proteins c-akt / metabolism
-
Pyrazoles / chemistry*
-
Pyridines / chemical synthesis
-
Pyridines / chemistry*
-
Pyridines / pharmacology
-
Transplantation, Heterologous
Substances
-
Antineoplastic Agents
-
Phosphoinositide-3 Kinase Inhibitors
-
Protein Kinase Inhibitors
-
Pyrazoles
-
Pyridines
-
3-Phosphoinositide-Dependent Protein Kinases
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt
-
pyridine