The discovery of new and more potent chloropyramine (C4) analogues for the potential treatment of invasive breast cancer

Abstract

Breast cancer (BC) is the second most common cancer worldwide, accounting for 25% of all female cancers. Although the survival rate has increased significantly in the past few decades, patients who develop secondary site metastasis as well as those diagnosed with triple negative breast cancer (TNBC) still represent a real unmet medical challenge. Previous studies have shown that chloropyramine (C4) inhibits FAK-VEGFR3 signaling. More recently, C4 is reported to have SASH1 inducing properties. However, C4 exerts its antitumour and antiangiogenic effects at high micromolar concentrations (>100 μM) that would not be compatible with further drug development against invasive breast cancer driven by FAK signaling. In this study, molecular modeling guided structural modifications have been introduced to the chloropyramine C4 scaffold to improve its activity in breast cancer cell lines. Seventeen compounds were designed and synthesised and their anti-proliferative activity was evaluated against three human breast cancer lines (MDA-MB-231, BT474 and T47D). Compound 5c was identified to display an average activity of IC₅₀ = 23.5- 31.3 μM, which represents a significant improvement of C4 activity in the same assay model. Molecular modelling and pharmacokinetic studies provided more promising insights into the mechanistic features of this new series.

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• 17 New chloropyramine (C4) analogues were designed and synthesised.

• All new compounds were evaluated for their activity in three different breast cancer cell lines.

• For the most active compound 5c, in vitro pharmacokinetic studies were performed.

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