Abstract 4533: New antimicrotubule phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonate prodrugs bioactivated selectively in breast cancer cells by CYP1A1: An innovative approach for the personalized treatment of breast cancer
Bibliographic record
Abstract
Abstract Breast cancers are the most common cancers among American women. Unfortunately, they are patient developing chemoresistance against conventional treatments or are diagnosed with more aggressive tumours and poorer prognosis. Novel therapeutic approaches are therefore required to treat patients that do not respond to current therapies. To this end, we developed a new family of highly potent antimitotics referred to as phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs). To improve the biopharmaceutical properties of these new antimicrotubule agents, we modified their 1-phenylimidazolidin-2-one moiety by substituting the -NH group of the imidazolidone moiety with linear and branched alkyl chains that lead to prodrugs referred to as phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs). PAIB-SOs are highly selective (ratio >1000) and cytocidal toward specific hormono-, non-hormono- and chemoresistant human breast cancer cells such as MCF-7, SK-BR-3, T47D and the “triple negative” MDA-MB-468 cells. PAIB-SOs arrest cell cycle progression in G2/M phase and disrupt the cytoskeleton in sensitive lines. Co-incubation of PAIB-SOs such as 22, with CYP1A1 inhibitors at subtoxic concentrations with MDA-MB-468 cells significantly reduced their antiproliferative activity. Moreover, using the ethoxyresorufin-O-deethylase assay and CYP1A1 Supersome™, 22 shows high affinity toward CYP1A1 and its selective biotransformation into its parent cytocidal PIB-SO (CEU-602). Furthermore, 22 induces CYP1A1 expression in MCF7 by 3-folds. Finally, 22 was also found to be active in vivo in a CAM assay on HT-1080 cells stably transfected with CYP1A1 while being inactive in the same cell line not expressing CYP1A1. These results suggest that PAIB-SO are prodrugs that could be use as an innovative approach for future personalized breast cancer treatments. Cytocidal activity and selectivity of CEU-602 and 22 on several human breast cancer cell linesDrugIC50 (nM)IC50 (nM)IC50 (nM)IC50 (nM)IC50 (nM)Selectivity ratioMCF7MDA-MB-468T47DSK-BR-3MDA-MB-231MDA-MB-231/SK-BR-3CEU-6023.14.66.23.16.42.1225.510202.05 9002 950 Citation Format: René C.-Gaudreault, Mathieu Gagné-Boulet, Xavier Charest-Morin, Jacques Lacroix, Marie-France Côté, Stéphane Gobeil, Sébastien Fortin, Coraline Lauvaux. New antimicrotubule phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonate prodrugs bioactivated selectively in breast cancer cells by CYP1A1: An innovative approach for the personalized treatment of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4533. doi:10.1158/1538-7445.AM2015-4533
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".