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
Authors: C.-Gaudreault René , Gagné-Boulet Mathieu , Charest-Morin Xavier , Lacroix Jacques , Côté Marie-France , Gobeil Stéphane , Fortin Sébastien , Lauvaux Coraline 
Published: August 2015

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 &gt;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