School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Cardiff, Wales, UK.
Chem Biol Drug Des. 2018 Jan;91(1):314-321. doi: 10.1111/cbdd.13083. Epub 2017 Aug 30.
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 IC = 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.
乳腺癌是全球第二常见的癌症，占所有女性癌症的 25%。尽管在过去几十年中，生存率有了显著提高，但发生二次转移的患者以及被诊断为三阴性乳腺癌的患者仍然代表着一个真正未满足的医疗挑战。先前的研究表明，氯吡拉敏（C4）抑制 FAK-VEGFR3 信号。最近，有报道称 C4 具有 SASH1 诱导特性。然而，C4 在高微摩尔浓度（>100μm）下发挥其抗肿瘤和抗血管生成作用，这与针对由 FAK 信号驱动的侵袭性乳腺癌的进一步药物开发不兼容。在这项研究中，引入了分子建模指导的结构修饰，以提高 C4 支架在乳腺癌细胞系中的活性。设计并合成了十七种化合物，并评估了它们对三种人乳腺癌细胞系（MDA-MB-231、BT474 和 T47D）的增殖活性。化合物 5c 被鉴定为显示出平均 IC 50 = 23.5-31.3μm 的活性，这代表在相同的测定模型中 C4 活性的显著提高。分子建模和药代动力学研究为这一系列的机制特征提供了更有前途的见解。
