Design, Synthesis and Biological Evaluation of Novel Osimertinib-Based HDAC and EGFR Dual Inhibitors

Herein a novel series of histone deacetylases (HDACs) and epidermal growth factor receptor (EGFR) dual inhibitors were designed and synthesized based on the structure of the approved EGFR inhibitor osimertinib (AZD9291). Among them, four compounds 5D, 5E, 9D and 9E exhibited more potent total HDAC inhibition than the approved HDAC inhibitor SAHA. However, these compounds only showed moderate to low inhibitory potency towards EGFR with compounds 5E and 9E possessing IC50 values against EGFR(WT) and EGFRT(790M) in the micromolar range. 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay revealed the potent antiproliferative activities of compounds 5D, 5E, 9D and 9E, among which 9E was even more potent against HeLa, MDA-MB-231, MDA-MB-468, HT-29 and KG-1 cell lines than SAHA and AZD9291. Further selectivity profile of 9E showed that this compound was not active against other 13 cancer-related kinases and two epigenetic targets lysine specific demethylase 1 (LSD1) and bromodomain-containing protein 4 (BRD4). These results support further structural modification of 9E to improve its EGFR inhibitory activity, which will lead to more potent and balanced HDAC and EGFR dual inhibitors as anticancer agents.