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

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

  • Eur J Med Chem. 2021 Jun 5:218:113392. doi: 10.1016/j.ejmech.2021.113392.
Xin-Hui Zhang 1,  Hui-Qin Kang 1,  Yuan-Yuan Tao 1,  Yi-Han Li 1,  Jun-Ru Zhao 1,  Ya-Gao 2,  Li-Ying Ma 3,  Hong-Min Liu 4
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China.
  • 2 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China. Electronic address: ya_gao@zzu.edu.cn.
  • 3 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China; China Meheco Topfond Pharmaceutical Co., Ltd, Zhumadian, 463000, PR China. Electronic address: maliying@zzu.edu.cn.
  • 4 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China. Electronic address: liuhm@zzu.edu.cn.
PMID: 33831778 DOI: 10.1016/j.ejmech.2021.113392
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 (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 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.

Keywords

1,2,4-Triazole; Bioisostere; Gastric cancer; HDAC6.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z