Blocking UV‐Induced eIF2α Phosphorylation with Small Molecule Inhibitors of GCN2
Why this work is in the frame
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Bibliographic record
Abstract
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.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it