# IBCar: Potent Orally Bioavailable Methyl N-[5-(3′-Iodobenzoyl)-1H-Benzimidazol-2-yl]Carbamate for Breast Cancer Therapy

## TL;DR

IBCar is a new, safe drug that effectively targets breast cancer cells while sparing normal cells, showing strong antitumor effects in mice.

## Contribution

A novel anti-microtubule agent, IBCar, is introduced with potent, selective cytotoxicity and safety in breast cancer models.

## Key findings

- IBCar caused irreversible microtubule depolymerization and mitochondrial dysfunction in breast cancer cells.
- Normal cells showed reversible effects and activated survival pathways in response to IBCar.
- Oral IBCar exhibited strong antitumor activity in mouse models of Luminal B and triple-negative breast cancer.

## Abstract

Approximately 30–40% of breast cancer patients treated with conventional chemotherapy experience side effects that significantly diminish their quality of life. The development of effective, nontoxic alternatives remains the leading unmet need in breast cancer care. Here, we describe a novel, safe anti-microtubule agent, methyl N-[5-(3′-iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (IBCar), which has demonstrated efficacy across a range of in vitro and in vivo breast cancer models.

Objectives: To investigate the efficacy and underlying mechanisms of IBCar’s biological activity in breast cancer models, both in cell culture and in mice, and to compare its effects on cancer versus normal cells. Methods: The cytotoxicity of IBCar was evaluated using the MTS assay to assess metabolic activity and the clonogenic assay to determine reproductive integrity. The impact of IBCar on microtubule integrity, mitochondrial function, and multiple signaling pathways was analyzed using Western blotting, microarray analysis, and live cell imaging. The therapeutic effectiveness of orally administered IBCar was assessed in a transgenic mouse model of Luminal B breast cancer and in mice implanted with subcutaneous triple-negative breast cancer xenografts. Results: IBCar demonstrated potent cytotoxicity across a diverse panel of breast cancer cell lines, including those with mutant or wild-type TP53, and cell lines with short and long doubling times. Comparative analysis revealed distinct responses between normal and cancer cells, including differences in IBCar’s effects on the mitochondrial membrane potential, endoplasmic reticulum stress and activation of cell death pathways. In breast cancer cells, IBCar was cytotoxic at nanomolar concentrations, caused irreversible microtubule depolymerization leading to sustained mitochondrial dysfunction, endoplasmic reticulum stress, and induced apoptosis. In normal cells, protective mechanisms included reversible microtubule depolymerization and activation of pro-survival signaling via the caspase-8 and riptosome pathways. The therapeutic potential of IBCar was confirmed in mouse models of Luminal B and triple negative BC, where it exhibited strong antitumor activity without detectable toxicity. Conclusions: These findings collectively support IBCar as a promising, effective, and safe therapeutic candidate for breast cancer treatment.