SAG1.3-derived Frizzled-targeting small-molecule compounds
Bibliographic record
Abstract
Exaggerated Wingless/Int1 (WNT)/Frizzled (FZD) signaling contributes to pathologies including fibrosis and different forms of cancers. Thus, targeting FZDs as WNT receptors for therapeutic purposes constitutes a promising intervention if the imminent risk of unwanted side effects caused by the involvement of WNT/FZD signaling in stem cell regulation and tissue homeostasis can be controlled. Here, we derivatize SAG1.3, which acts through FZD 6 as a partial agonist. Screening of SAG1.3 derivatives identified compound 11 that competed with BODIPY-cyclopamine binding at different FZDs and inhibited WNT-induced FZD dynamics and β-catenin signaling in HEK293 cells. Furthermore, compound 11 blocked WNT-3A-induced Lgr5 gene expression in human primary hepatocyte spheroids and reduced the viability of RNF43-mutated but not RNF43-wildtype pancreatic cancer cells. Based on our data, we suggest that compound 11 acts on FZDs to limit WNT- and WNT-surrogate-induced receptor dynamics providing a valid proof-of-concept for targeting FZDs with small molecule compounds.
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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 | 0.000 | 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) | 0.001 | 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".