An Adenosine Analogue Library Reveals Insights into Active Sites of Protein Arginine Methyltransferases and Enables the Discovery of a Selective PRMT4 Inhibitor
Bibliographic record
Abstract
Protein arginine methyltransferases (PRMTs) represent promising drug targets. However, the lack of isoform-selective chemical probes poses a significant hurdle in deciphering their biological roles. To address this issue, we devised a library of 100 diverse adenosine analogues, enabling a detailed exploration of the active site of PRMTs. Despite their close homology, our analysis unveiled specific chemical trends unique to the individual members. Notably, compound YD1130 demonstrated over 1000-fold selectivity for PRMT4 (IC 50 < 0.5 nM) over a panel of 38 methyltransferases, including the other PRMTs. Its prodrug YD1342 exhibited potent inhibition on cellular substrate methylation, breast cancer cell colony formation, and tumor growth in the animal model, surpassing or matching known PRMT4-specific inhibitors. In summary, our focused library not only illuminates the intricate active sites of PRMTs to facilitate the discovery of highly potent and isoform-selective probes but also offers a versatile blueprint for identifying chemical probes for other methyltransferases.
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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) | 0.000 | 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".