Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer.
Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer.
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新型尿素化合物作为FGFR1抑制剂的设计，合成和结构活性关系研究，用于治疗转移性三阴性乳腺癌。
DOI：
10.1016/j.ejmech.2020.112866
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发表时间：
2021-01-01
影响因子：
6.7
通讯作者：
German NA
中科院分区：
文献类型：
--
作者：
Ashraf-Uz-Zaman M;Shahi S;Akwii R;Sajib MS;Farshbaf MJ;Kallem RR;Putnam W;Wang W;Zhang R;Alvina K;Trippier PC;Mikelis CM;German NA
三阴性乳腺癌（TNBC）是一种侵袭性癌症，具有较高的转移率和复发率，约三分之一的三阴性乳腺癌患者会发生脑转移。同时，三阴性乳腺癌对化疗反应良好，这一特点促使人们在该领域寻找具有治疗潜力的新化合物。最近，我们发现了新型脲基化合物，其对特定细胞系具有细胞毒性，且在体内能够穿过血脑屏障。我们合成并分析了一个包含40多种化合物的库，以阐明产生所观察到活性的关键特征。我们还确定成纤维细胞生长因子受体1（FGFR1）是受这些化合物影响的分子靶点，并通过计算机模拟模型证实了我们的数据。总体而言，我们设想这些化合物可进一步开发，用于潜在治疗转移性乳腺癌。
Triple-negative breast cancer (TNBC) is an aggressive type of cancer characterized by higher metastatic and reoccurrence rates, where approximately one-third of TNBC patients suffer from the metastasis in the brain. At the same time, TNBC shows good responses to chemotherapy, a feature that fuels the search for novel compounds with therapeutic potential in this area. Recently, we have identified novel urea-based compounds with cytotoxicity against selected cell lines and with the ability to cross the blood-brain barrier in vivo. We have synthesized and analyzed a library of more than 40 compounds to elucidate the key features responsible for the observed activity. We have also identified FGFR1 as a molecular target that is affected by the presence of these compounds, confirming our data using in silico model. Overall, we envision that these compounds can be further developed for the potential treatment of metastatic breast cancer.
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