Abstract 1359: Evaluation of the therapeutic potential of AIMZ-938 as a new cytochrome p450 1A1-selective prodrug for the treatment of breast cancers

Abstract

Abstract Breast cancers (BC) are the most common cancers among women in North America. Several BC show high relapse rates or chemoresistance to current chemotherapies. Hence it is essential to develop new therapies to cure BC that would otherwise be lethal due to the absence of alternative treatments. To get around this issue, we developed AIMZ-938, a phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonate, member of a novel class of cytochrome P450 1A1 (CYP1A1)-dependent prodrugs releasing selective and highly cytotoxic antimitotic metabolites in BC tumors expressing CYP1A1. AIMZ-938 does not exhibit toxicity in normal cells not expressing CYP1A1, a property that protects normal tissues from chemotherapy-derived side effects. The aims of our work are to evaluate in mouse models 1) the maximal tolerated dose of AIMZ-938, 2) its half-life (t1/2) and 3) its antitumor activity in a xenograft model of BC. The maximal tolerated dose (MTD) of AIMZ-938 and its t1/2 were assessed on CD-1 female mice. The MTD of AIMZ-938 was evaluated at a concentration of 0.5 mg/mL with a sequential increase of 1/2 logarithmic value until the MTD was reached. AIMZ-938 was administered to mice as a single IV dose at the MTD concentration and t1/2 was evaluated using collected blood samples obtained through a terminal cardiac puncture at 0, 30, 60, 120, 240, 480, 960 and 1440 minutes. The AIMZ-938 concentrations were quantified by UHPLC-UV. Then, the antitumor activity of AIMZ-938 was assessed using a MCF7 xenograft CD-1 female nude mouse model. Briefly, the human breast cancer model was produced by a subcutaneous implantation of a 17 beta-estradiol pellet in each animal flank followed by the inoculation of MCF7 cells one week later in the opposite flank. When the tumors reached a volume of 50-100 mm3, AIMZ-938 was administered IV biweekly to the animals for three weeks. Paclitaxel was used as positive control and was administered weekly for three weeks while a saline solution and the vehicle were used as negative controls. The tumor growth was measured biweekly using a metric Vernier caliper and the evaluation of the side effects was conducted daily. Our results showed that AIMZ-938 is sparingly soluble in our vehicle (0.8 mg/mL) and this concentration was fixed for further administrations. Half-life of IV administered AIMZ-938 was 11.5 ± 1.1 h, strongly suggesting that this compound is suitable for further pharmacodynamic studies. Moreover, AIMZ-938 did not exhibit significant side effects in animals at its highest concentration (0.8 mg/mL) when administered IV biweekly for 3 weeks. Finally, AIMZ-938 exhibited potent antitumor activity, similar to paclitaxel, a standard first-line treatment for breast cancer. AIMZ-938 is highly potent and a promising new targeted antimitotic prodrug for the treatment of breast cancers expressing CYP1A1. Citation Format: Atziri Corin Chavez Alvarez, Chahrazed Bouzriba, Mathieu Gagné-Boulet, Sylvie Pilote, René C.-Gaudreault, Chantale Simard, Sébastien Fortin. Evaluation of the therapeutic potential of AIMZ-938 as a new cytochrome p450 1A1-selective prodrug for the treatment of breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1359.