Blocking UV-induced eIF2alpha phosphorylation with small molecule inhibitors of GCN2.
The eIF2alpha 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 eIF2alphain 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.
Robert
Francis
F
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Williams
Chris
C
Yan
Yifei
Y
Donohue
Elizabeth
E
Cencic
Regina
R
Burley
Stephen K
SK
Pelletier
Jerry
J
D000818:Animals; D000873:Anthracenes / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D005347:Fibroblasts / Q000528:radiation effects; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D014466:Ultraviolet Rays
D000873:Anthracenes; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C432165:pyrazolanthrone; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases