Premium
Blocking UV‐Induced eIF2α Phosphorylation with Small Molecule Inhibitors of GCN2
Author(s) -
Robert Francis,
Williams Chris,
Yan Yifei,
Donohue Elizabeth,
Cencic Regina,
Burley Stephen K.,
Pelletier Jerry
Publication year - 2009
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00827.x
Subject(s) - kinase , long term potentiation , translation (biology) , phosphorylation , biology , in vivo , microbiology and biotechnology , integrated stress response , biochemistry , eif2 , chemistry , receptor , genetics , messenger rna , gene
The eIF2α kinase general control non‐depressible 2 integrates translation initiation rates to amino acid availability. General control non‐depressible 2 also regulates translation initiation during synaptic plasticity and GCN2 −/− mice show improved memory compared with wild‐type mice with a reduced threshold for triggering late long‐term potentiation. This property suggests that inhibiting general control non‐depressible 2 function might represent a therapeutic avenue for improving memory. We screened for general control non‐depressible 2 inhibitors using a small library of known kinase inhibitors and ATP‐analogs and identified three compounds – indirubin‐3′‐monoxime, SP600125 and a SyK inhibitor with activity against general control non‐depressible 2. All three compounds inhibit the ability of general control non‐depressible 2 to phosphorylate eIF2α in vitro as well as in vivo following UV‐treatment of mouse embryonic fibroblasts. Using computer‐assisted modeling, we modeled the binding of the inhibitors in the ATP‐binding site of general control non‐depressible 2. This work provides the molecular basis for undertaking structure–activity relationships of these compounds in order to develop specific inhibitors of general control non‐depressible 2.