Identification and Characterization of Small Molecule Inhibitors of Polynucleotide Kinase 3'-Phosphatase
Bibliographic record
Abstract
DNA lesions arise constantly in cells and are repaired by a variety of DNA repair pathways. Polynucleotide kinase 3’-phosphatase (PNKP) aids repair by phosphorylating 5’-hydroxyl DNA termini and dephosphorylating 3’-phosphate DNA termini for the completion of repair by DNA ligases. This activity is critical in vivo because DNA breaks do not usually possess ligatable termini. PNKP knockdown sensitizes cells to several DNA damaging agents, including the topoisomerase I (TOP1) inhibitor camptothecin - analogs of which are being developed into chemotherapeutic drugs - because the resolution of stalled TOP1-DNA complexes requires processing by PNKP. We hypothesize that small molecule inhibitors of PNKP could bolster the effects of radio- and chemotherapies on cancer cells. I have identified eight compounds that effectively inhibit human PNKP and, with reduced potency, T4 PNK in vitro. These compounds act by reversibly inhibiting the substrate-enzyme interaction but they do not appear to sensitize U2OS cells to camptothecin.
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".