2. Academic Validation
  3. Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases

Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases

  • J Biol Chem. 2009 Oct 9;284(41):28392-28400. doi: 10.1074/jbc.M109.038984.
Wolfgang Link 1,  Julen Oyarzabal 1,  Beatriz G Serelde 1,  Maria Isabel Albarran 1,  Obdulia Rabal 1,  Antonio Cebriá 1,  Patricia Alfonso 1,  Jesus Fominaya 1,  Oliver Renner 1,  Sandra Peregrina 1,  David Soilán 1,  Plácido A Ceballos 1,  Ana-Isabel Hernández 1,  Milagros Lorenzo 1,  Paolo Pevarello 1,  Teresa G Granda 1,  Guido Kurz 1,  Amancio Carnero 1,  James R Bischoff 2
Affiliations

Affiliations

  • 1 Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
  • 2 Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Electronic address: jrbischoff@cnio.es.
PMID: 19690175 DOI: 10.1074/jbc.M109.038984
Abstract

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.

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