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

Kandil, Sahar, Prencipe, Filippo, Jones, Samuel, Hiscox, Stephen and Westwell, Andrew D. 2018. The discovery of new and more potent chloropyramine (C4) analogues for the potential treatment of invasive breast cancer. Chemical Biology and Drug Design 91 (1) , pp. 314-321. 10.1111/cbdd.13083

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Breast cancer 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 still represent a real unmet medical challenge. Previous studies have shown that chloropyramine (C4) inhibits FAK-VEGFR3 signalling. 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 signalling. In this study, molecular modelling 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 synthesized, and their antiproliferative 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Wiley-Blackwell
ISSN: 1747-0277
Date of First Compliant Deposit: 31 August 2017
Date of Acceptance: 27 July 2017
Last Modified: 25 Aug 2020 13:59

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