A tale of two mechanisms: The p53 modulator COTI-2 is a Zn metallochaperone
Bibliographic record
Abstract
ABSTRACT Mutations in, or misregulation of, Tp53 are found in approximately 50% of all cancers. p53 functions by ensuring that cells with irretrievably damaged DNA undergo apoptosis. Tp53 mutations often induce conformational changes that inhibit activity; however, small‐molecule chaperones could theoretically restore conformation and activity. COTI‐2, a thiosemicarbazone with orphan‐drug status for ovarian cancer, has proven an effective cytotoxic agent against various cancer cell lines in vitro , exhibited efficacy in vivo , and has demonstrated a good safety profile in Phase 1b human clinical trials. The proposed mechanism, direct engagement and refolding of mutant p53, has been supported by a combination of cell‐based assays and transcriptomics data. Through a combination of experimental and computational approaches, we demonstrate that this is an unlikely mechanism of action, and that COTI ‐2 instead likely acts as a selective, well‐tolerated, zinc chaperone to replace zinc ions lost to p53 mutants' deficient zinc‐binding.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.005 |
| Scholarly communication | 0.006 | 0.014 |
| Open science | 0.002 | 0.004 |
| Research integrity | 0.005 | 0.008 |
| Insufficient payload (model declined to judge) | 0.009 | 0.003 |
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 source (direct Gemma or distilled Codex), 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".