Targeting IL-6/STAT3 pathway with small-molecule compounds for multiple sclerosis therapy (THER6P.849)
Bibliographic record
Abstract
Abstract Multiple Sclerosis is an immune-mediated chronic CNS disease where IL-6/STAT3 pathway plays a critical role in disease pathogenesis. Dysregulated IL-6/STAT3 signaling skews Teff/Treg balance toward an enhanced T effector response, favoring the development of CNS autoimmunity. Specifically, we previously showed IL-6 induces the development of highly encephalitogenic Th17 cells, suggesting IL-6/STAT3 pathway may serve as an innovative target. In support of this strategy, both IL-6-/- and STAT3-/- mice are completely resistant to EAE. Therefore, we designed four small-molecule lead compounds targeting IL-6/STAT3 pathway. MDL-5 and MDL-16 bind to the D1 domain of GP130, preventing the IL-6/GP130 interaction; while LLL-12 and LY-5 bind to the SH2 domain of STAT3, preventing STAT3 phosphorylation. All four lead compounds significantly inhibit IL-6 induced IL-17 production in myelin-specific CD4 T cells without significant toxicity. Furthermore, adoptive transfer of small-molecule treated myelin-specific CD4 T cells into naïve recipient mice show a significant reduction in EAE severity compared to control group, suggesting these compounds suppress the encephalitogenicity of CD4 T cells. More importantly, immunized small-molecule treated mice demonstrate delayed onset and reduced severity compared to control mice, suggesting in vivo treatment suppresses EAE development. Together, our data suggest that these four lead compounds have great potential to serve as an innovative therapy.
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How this classification was reachedexpand
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 | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".