Targeting an EGFR Water Network with 4‐Anilinoquin(az)oline Inhibitors for Chordoma
Why this work is in the frame
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Bibliographic record
Abstract
Abstract Quinoline‐ and quinazoline‐based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non‐small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure–activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [ N ‐(3‐ethynylphenyl)‐6,7‐dimethoxyquinolin‐4‐amine], 4 [ N ‐(3‐ethynylphenyl)‐6,7‐dimethoxyquinazolin‐4‐amine], and 7 [4‐((3‐ethynylphenyl)amino)‐6,7‐dimethoxyquinoline‐3‐carbonitrile]. We also identified 6,7‐dimethoxy‐ N ‐(4‐((4‐methylbenzyl)oxy)phenyl)quinolin‐4‐amine (compound 18 ), which is the most potent inhibitor (IC 50 =310 n m ) of the UCH‐2 chordoma cell line to date.
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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 it