Thieno[3,2‐<i>b</i>]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode
Bibliographic record
Abstract
Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2-b]pyridine scaffold. The weak interaction of the thieno[3,2-b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome-wide selectivity, as illustrated by the isomers MU1464 and MU1668. Thus, this core structure provides a template of ATP-competitive but not ATP-mimetic inhibitors that are anchored at the kinase back pocket. Mapping the chemical space around the central thieno[3,2-b]pyridine pharmacophore afforded highly selective inhibitors of the kinase Haspin, exemplified by the compound MU1920 that fulfils criteria for a quality chemical probe and is suitable for use in in vivo applications. However, despite the role of Haspin in mitosis, the inhibition of Haspin alone was not sufficient to elicit cytotoxic effect in cancer cells. The thieno[3,2-b]pyridine scaffold can be used in a broader context, as a basis of inhibitors targeting other underexplored protein kinases, such as CDKLs.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".