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The discovery of new and more potent chloropyramine (C4) analogues for the potential treatment of invasive breast cancer
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2017-08-30 07:05:54 , DOI: 10.1111/cbdd.13083 Sahar Kandil 1 , Filippo Prencipe 1 , Samuel Jones 1 , Stephen Hiscox 1 , Andrew D Westwell 1
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2017-08-30 07:05:54 , DOI: 10.1111/cbdd.13083 Sahar Kandil 1 , Filippo Prencipe 1 , Samuel Jones 1 , Stephen Hiscox 1 , Andrew D Westwell 1
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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.
中文翻译：
发现新的和更有效的氯吡胺 (C4) 类似物可用于治疗浸润性乳腺癌
乳腺癌是全球第二大常见癌症，占所有女性癌症的 25%。尽管在过去几十年中生存率显着提高，但发生继发部位转移的患者以及被诊断为三阴性乳腺癌的患者仍然是一个真正未得到满足的医学挑战。先前的研究表明，氯吡胺 ( C4 ) 抑制 FAK-VEGFR3 信号传导。最近，据报道C4具有 SASH1 诱导特性。然而，C4在高微摩尔浓度（>100 μ m) 这与 FAK 信号驱动的针对侵袭性乳腺癌的进一步药物开发不兼容。在这项研究中，分子建模指导的结构修饰已被引入氯吡胺C4支架，以提高其在乳腺癌细胞系中的活性。设计和合成了 17 种化合物，并针对三种人类乳腺癌细胞系（MDA-MB-231、BT474 和 T47D）评估了它们的抗增殖活性。化合物5c经鉴定显示 IC 50 = 23.5–31.3 μ m的平均活性，这代表了C4的显着改善在同一测定模型中的活性。分子建模和药代动力学研究为这个新系列的机制特征提供了更有希望的见解。
更新日期：2017-09-21
中文翻译：
发现新的和更有效的氯吡胺 (C4) 类似物可用于治疗浸润性乳腺癌
乳腺癌是全球第二大常见癌症，占所有女性癌症的 25%。尽管在过去几十年中生存率显着提高，但发生继发部位转移的患者以及被诊断为三阴性乳腺癌的患者仍然是一个真正未得到满足的医学挑战。先前的研究表明，氯吡胺 ( C4 ) 抑制 FAK-VEGFR3 信号传导。最近，据报道C4具有 SASH1 诱导特性。然而，C4在高微摩尔浓度（>100 μ m) 这与 FAK 信号驱动的针对侵袭性乳腺癌的进一步药物开发不兼容。在这项研究中，分子建模指导的结构修饰已被引入氯吡胺C4支架，以提高其在乳腺癌细胞系中的活性。设计和合成了 17 种化合物，并针对三种人类乳腺癌细胞系（MDA-MB-231、BT474 和 T47D）评估了它们的抗增殖活性。化合物5c经鉴定显示 IC 50 = 23.5–31.3 μ m的平均活性，这代表了C4的显着改善在同一测定模型中的活性。分子建模和药代动力学研究为这个新系列的机制特征提供了更有希望的见解。
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