Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases.
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.
Link
Wolfgang
W
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Oyarzabal
Julen
J
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Serelde
Beatriz G
BG
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Albarran
Maria Isabel
MI
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Rabal
Obdulia
O
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Cebriá
Antonio
A
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Alfonso
Patricia
P
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Fominaya
Jesus
J
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Renner
Oliver
O
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Peregrina
Sandra
S
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Soilán
David
D
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Ceballos
Plácido A
PA
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Hernández
Ana-Isabel
AI
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Lorenzo
Milagros
M
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Pevarello
Paolo
P
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Granda
Teresa G
TG
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Kurz
Guido
G
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Carnero
Amancio
A
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Bischoff
James R
JR
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Electronic address: jrbischoff@cnio.es.
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002867:Chromones / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005663:Furans / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D009025:Morpholines / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D002867:Chromones; D004791:Enzyme Inhibitors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005663:Furans; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; C544684:ETP 45658; C499517:FOXO3 protein, human; C522973:PI103; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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