Identification of a 2‐phenylthiazole derivative acetylcholinesterase modulator with in vitro antitumor activity in breast cancer cells

Abstract Acetylcholinesterase (AchE) is a serine hydrolase with classical function to degrade acetylcholine and terminate neurotransmission. While “nonclassical” functions of AchE were involved in cell growth, death, invasion, etc. The expression and activity of AchE is changed in tumors, suggesting AChE inhibitors (AchEIs) may serve as potential antitumor drugs. In this study, the antitumor activity of a series of 2‐phenylthiazole derivatives originally designed and synthesized as AchEIs were investigated. One compound named A6, was screened out with superior antitumor efficacy, especially against breast cancer MCF‐7 cells. A6 significantly disrupted the amino acid metabolism and inhibited migration of MCF‐7. In addition, A6 induced apoptosis of MCF‐7 cells. To clarify how A6 affected on MCF‐7 cells, RNA‐seq analysis was conducted to evaluate the whole genome effect of A6 on gene expression. A total of 153 genes were increased, and the expression of 81 genes was decreased. GO and KEGG enrichment analysis showed A6 treatment mainly disrupted sterol/cholesterol pathway, Ras signaling pathway, VEGF signaling pathway, etc. Moreover, bioinformatic analysis and cell viability test showed A6 plays anticancer role by regulating Best1 and HIST1H2BJ. These results indicate that AchEI A6 could be a potential antitumor agent for breast cancer patients and could help the development of novel therapies.