Identification of novel 1,3-diaryl-1,2,4-triazole-capped histone deacetylase 6 inhibitors with potential anti-gastric cancer activity

Histone deacetylase 6 (HDAC6) has emerged as a critical regulator of many cellular pathways in tumors due to its unique structure basis and abundant substrate types. Over the past few decades, the role played by HDAC6 inhibitors as anticancer agents has sparked great interest of biochemists worldwide. However, they were less reported for gastric cancer therapy. In this paper, with the help of bioisosteric replacement, in-house library screening, and lead optimization strategies, we designed, synthesized and verified a series of 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors with promising anti-gastric cancer activities. Amongst, compound 9r displayed the best inhibitory activity towards HDAC6 (IC50 = 30.6 nM), with 128-fold selectivity over HDAC1. Further BLI and CETSA assay proved the high affinity of 9r to HDAC6. In addition, 9r could dose-dependently upregulate the levels of acetylated alpha-tubulin, without significant effect on acetylated histone H3 in MGC803 cells. Besides, 9r exhibited potent antiproliferative effect on MGC803 cells, and promoted apoptosis and suppressed the metastasis without obvious toxicity, suggesting 9r would serve as a potential lead compound for the development of novel therapeutic agents of gastric cancer. (c) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

In this study, a series of 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors were designed, synthesized and verified, with compound 9r showing the best inhibitory activity with potential for gastric cancer therapy. The high selectivity and affinity of 9r to HDAC6, along with its ability to upregulate acetylated alpha-tubulin levels and exhibit antiproliferative and anti-metastatic effects without significant toxicity, suggest that 9r could serve as a lead compound for the development of novel therapeutic agents for gastric cancer.