Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer

新型尿素化合物作为FGFR1抑制剂治疗转移性三阴性乳腺癌的设计、合成及构效关系研究

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作者:Md Ashraf-Uz-Zaman, Sadisna Shahi, Racheal Akwii, Md Sanaullah Sajib, Mohammad Jodeiri Farshbaf, Raja Reddy Kallem, William Putnam, Wei Wang, Ruiwen Zhang, Karina Alvina, Paul C Trippier, Constantinos M Mikelis, Nadezhda A German

Abstract

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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