1. Identification of novel 1,3-diaryl-1,2,4-triazole-capped histone deacetylase 6 inhibitors with potential anti-gastric cancer activity.
- Author
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Zhang XH, Kang HQ, Tao YY, Li YH, Zhao JR, Ya-Gao, Ma LY, and Liu HM
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Histone Deacetylase 6 metabolism, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors chemistry, Humans, Male, Mice, Mice, Inbred C57BL, Molecular Structure, Stomach Neoplasms metabolism, Stomach Neoplasms pathology, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles chemistry, Antineoplastic Agents pharmacology, Histone Deacetylase 6 antagonists & inhibitors, Histone Deacetylase Inhibitors pharmacology, Stomach Neoplasms drug therapy, Triazoles pharmacology
- Abstract
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 (IC
50 = 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 α-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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)- Published
- 2021
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