SMYD3 is a histone methyltransferase involved in transcriptional regulation, and its overexpression in various forms of cancer justifies that blocking SMYD3 functions can serve as a novel therapeutic strategy in cancer treatment. Herein, a series of novel tetrahydrofuranyl spirooxindoles were designed and synthesized based on a structure-based drug design strategy. Subsequent biochemical analysis suggested that these novel SMYD3 inhibitors showed good anticancer activity against stomach adenocarcinoma both in vitro and in vivo. Among them, compound 7r exhibited potent inhibitory capacities against SMYD3 and BGC823 cells with IC50 values of 0.81 and 0.75 μM, respectively. Mechanistic investigations showed that 7r could suppress Akt methylation and activation by SMYD3 and trigger lethal autophagic flux inhibition via the Akt-mTOR pathway. Collectively, our results may bridge the rational discovery of privileged structures, epigenetic targeting of SMYD3, and regulation of autophagic cell death.
Keywords: Lethal autophagy; SMYD3 inhibitors; Structure-activity relationship; Tetrahydrofuranyl spirooxindoles.
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