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- Title
Blocking UV-Induced eIF2α Phosphorylation with Small Molecule Inhibitors of GCN2.
- Authors
Robert, Francis; Williams, Chris; Yan, Yifei; Donohue, Elizabeth; Cencic, Regina; Burley, Stephen K.; Pelletier, Jerry
- Abstract
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.
- Subjects
PHOSPHORYLATION; NEUROPLASTICITY; CONNECTIVE tissue cells; IMINO acids; LABORATORY mice
- Publication
Chemical Biology & Drug Design, 2009, Vol 74, Issue 1, p57
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/j.1747-0285.2009.00827.x