Type II combi-molecules: design and binary targeting properties of the novel triazolinium-containing molecules JDD36 and JDE05
Why this work is in the frame
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Bibliographic record
Abstract
We recently designed molecules termed "type II combi-molecules" to block the epidermal growth factor receptor and to damage DNA without the requirement for hydrolytic cleavage. Here, we studied two such combi-molecules (JDD36 and JDE05), containing a novel quinazoline-linked chloroethyltriazolinium system. The epidermal growth factor receptor-targeting potential of these novel structures was studied by ELISA for isolated epidermal growth factor receptor and by Western blotting for whole-cell assays. DNA damage was analyzed using the single-cell microelectrophoresis comet assay. Antiproliferative effects were determined by the sulforhodamine B assay. JDD36 showed an IC50 of 0.6 micromol/l in the ELISA for epidermal growth factor receptor tyrosine kinase, a dose-dependent inhibition of epidermal growth factor receptor phosphorylation and significant levels of DNA damage in the human DU145 prostate cancer cell line. JDD36 was an overall 2- to 15-fold stronger antiproliferative agent than JDE05 that showed potent epidermal growth factor receptor inhibitory activity (IC50 epidermal growth factor receptor, 0.035 micromol/l) but weak DNA-damaging potential. In a panel of LNCaP erbB transfectants, in contrast to JDE05, JDD36 showed remarkable and selective potency against the LNCaPerbB2 transfectant. The results in toto suggest that the overall superior potency of JDD36 when compared with JDE05 may be imputed to its balanced binary epidermal growth factor receptor-DNA-targeting properties that may induce a tandem blockade of epidermal growth factor receptor-mediated mitogenic signaling while depleting alternative survival mechanism by damaging DNA.
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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