Discovery of Imidazo[1,2-<i>b</i>]pyridazine Derivatives as Potent and Highly Selective Irreversible Bruton’s Tyrosine Kinase (BTK) Inhibitors
Bibliographic record
Abstract
Bruton’s tyrosine kinase (BTK) is a crucial enzyme in the B cell receptor signaling pathway. It plays a central role in B cell development, maturation, and signaling. This role extends to the survival, proliferation, and migration of malignant B cells, making BTK an intriguing target in the search for therapeutics against B cell malignancies. Our research focused on the discovery of a covalent inhibitor of BTK with good selectivity and potency and a favorable safety profile. We identified compound 22, an imidazo[1,2- b ]pyridazine derivative, exhibiting potent BTK inhibition (IC 50 1.3 nM) with excellent selectivity across 310 kinases. Compound 22 demonstrated favorable pharmacokinetics and a robust safety profile. In a xenograft model, it significantly inhibited tumor growth, achieving complete tumor regression in 7 out of 10 mice at a dose of 15 mg/kg. This promising preclinical data led to the advancement of compound 22, named TM471-1, into Phase I clinical trials (CXHL2300956).
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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".