Chemical Interrogation of FOXO3a Nuclear Translocation Identifies Potent and Selective Inhibitors of Phosphoinositide 3-Kinases
| Autor: | Paolo Pevarello, Milagros Lorenzo, Teresa G. Granda, David Soilan, Sandra Peregrina, María Isabel Albarrán, Obdulia Rabal, Amancio Carnero, Beatriz G. Serelde, Patricia Alfonso, Antonio Cebriá, Plácido A. Ceballos, Julen Oyarzabal, Jesús Fominaya, Ana-Isabel Hernández, James R. Bischoff, Wolfgang Link, Guido Kurz, Oliver Renner |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Pyridines
Morpholines Active Transport Cell Nucleus Mice Transgenic Biology Biochemistry Pyrazolopyrimidine Cell Line Forkhead transcription factors chemistry.chemical_compound Mice Phosphatidylinositol 3-Kinases Animals Humans Furans Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Effector Akt/PKB signaling pathway Kinase Forkhead Box Protein O3 Mechanisms of Signal Transduction Enzyme inhibitors Proto-oncogene proteins c-akt Cell Biology Pyrimidines chemistry Chromones Recombinant fusion proteins Pyrazoles Female Signal transduction Cell nucleus Molecular structure Signal Transduction |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | 9 páginas, 4 figuras, 1 tabla. Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. A cell-based imaging assay that monitored the translocation of the Akt effector protein, Forkhead box O (FOXO), from the cytoplasm to the nucleus was employed to screen a collection of 33,992 small molecules. The positive compounds were used to screen kinases known to be involved in FOXO translocation. Pyrazolopyrimidine derivatives were found to be potent FOXO relocators as well as biochemical inhibitors of PI3Kalpha. A combination of virtual screening and molecular modeling led to the development of a structure-activity relationship, which indicated the preferred substituents on the pyrazolopyrimidine scaffold. This leads to the synthesis of ETP-45658, which is a potent and selective inhibitor of phosphoinositide 3-kinases and demonstrates mechanism of action in tumor cell lines and in vivo in treated mice. This work was supported by funding from the Spanish Ministerio de Ciencias e Innovación (Project BIO2006-02432). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|