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The discovery of new and more potent chloropyramine (C4) analogues for the potential treatment of invasive breast cancer
Author(s) -
Kandil Sahar,
Prencipe Filippo,
Jones Samuel,
Hiscox Stephen,
Westwell Andrew D.
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13083
Subject(s) - breast cancer , drug discovery , cancer , metastasis , cancer research , medicine , triple negative breast cancer , pharmacology , oncology , computational biology , chemistry , biology , bioinformatics
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 μ m ) 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 IC 50 = 23.5–31.3 μ m , 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.