PKIS Deep Dive Yields a Chemical Starting Point for Dark Kinases and a Cell Active BRSK2 Inhibitor
Bibliographic record
Abstract
Abstract The Published Kinase Inhibitor Set (PKIS) is a publicly-available chemogenomic library distributed to more than 300 laboratories by GlaxoSmithKline (GSK) between 2011–2015 and by SGC-UNC from 2015–2017. Screening this library of well-annotated, published kinase inhibitors has yielded a plethora of data in diverse therapeutic and scientific areas, funded applications, publications, and provided impactful pre-clinical results. Based on kinome-wide screening results, we report a thorough investigation of one PKIS compound, GW296115, as an inhibitor of several members of the Illuminating the Druggable Genome (IDG) list of understudied dark kinases. Specifically, GW296115 validates as a potent lead chemical tool that inhibits six IDG kinases with IC 50 values less than 100nM. Focused studies establish that GW296115 is cell active, and directly engages BRSK2. Further evaluation showed that GW296115 downregulates BRSK2-driven phosphorylation and downstream signaling. Summary Statement GW296115 inhibits understudied kinases, including BRSK2, with IC 50 values less than 100nM.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.009 | 0.005 |
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".