Exploring the Ligandability of 53BP1 Through Fragment-Based Approaches
Bibliographic record
Abstract
53BP1 is a DNA damage response protein recruited to sites of double strand breaks through recognition of dimethylated lysine on histone 4 by its tandem Tudor domains. Like 53BP1, BRCA-1 plays a role in the regulation of DNA repair pathways, and BRCA-1 mutations have been strongly linked to breast and ovarian cancer. Interestingly, mice null for 53BP1 and BRCA-1 genes display minimal tumor formation, suggesting that the effects of deleterious BRCA-1 mutations could be prevented with potent 53BP1 small molecule antagonists. Herein, we describe a fragment screen that was used to identify compounds that bind to the 53BP1 Tudor domain and a chemoinformatic workflow to select near-neighbour analogues and establish Structure Activity Relationships for these binders. The marked affinity improvements of the analogues over their parent fragments highlights the developability of these series and the utility of this approach in discovering novel hit compounds for 53BP1 and other methyl-lysine reader proteins.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".