EGFR) dual inhibitors were designed and synthesized based on the structure of the\napproved EGFR inhibitor osimertinib (AZD9291). Among them, four compounds 5D, 5E, 9D and 9E\nexhibited more potent total HDAC inhibition than the approved HDAC inhibitor SAHA. However,\nthese compounds only showed moderate to low inhibitory potency towards EGFR with compounds\n5E and 9E possessing IC50 values against EGFR^WT and EGFRT^790M in the micromolar range.\n3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay revealed the potent\nantiproliferative activities of compounds 5D, 5E, 9D and 9E, among which 9E was even more\npotent against HeLa, MDA-MB-231, MDA-MB-468, HT-29 and KG-1 cell lines than SAHA and\nAZD9291. Further selectivity profile of 9E showed that this compound was not active against\nother 13 cancer-related kinases and two epigenetic targets lysine specific demethylase 1 (LSD1) and\nbromodomain-containing protein 4 (BRD4). These results support further structural modification of\n9E to improve its EGFR inhibitory activity, which will lead to more potent and balanced HDAC and\nEGFR dual inhibitors as anticancer agents.
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