2. Academic Validation
  3. A novel aromatic amide derivative SY-65 co-targeted tubulin and histone deacetylase 1 with potent anticancer activity in vitro and in vivo

A novel aromatic amide derivative SY-65 co-targeted tubulin and histone deacetylase 1 with potent anticancer activity in vitro and in vivo

  • Biochem Pharmacol. 2022 Jul;201:115070. doi: 10.1016/j.bcp.2022.115070.
Yin-Ru Li 1,  Fang-Fang Liu 2,  Wen-Bo Liu 3,  Yi-Fan Zhang 3,  Xin-Yi Tian 1,  Xiang-Jing Fu 1,  Yan Xu 1,  Jian Song 4,  Sai-Yang Zhang 5
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, People's Republic of China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou 450001, People's Republic of China.
  • 4 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, People's Republic of China; School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou 450001, People's Republic of China. Electronic address: mumuandzz@163.com.
  • 5 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, People's Republic of China; School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou 450001, People's Republic of China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, Jiangsu, People's Republic of China. Electronic address: saiyangz@zzu.edu.cn.
PMID: 35526597 DOI: 10.1016/j.bcp.2022.115070
Abstract

Given the essential role of Epigenetic regulation in many biological processes, targeted epigenetic drugs have been gradually applied to the treatment of tumors. Histone deacetylases (HDACs) are a class of epigenetic Enzymes, which play key roles in chromosome structural modification and gene expression regulation. Targeted microtubules drugs have achieved great success in clinical application for decades. Development of novel agents with multitargeting capabilities specially dual-target has become a popular research field for the treatment of human cancers, which may provide synergistic Anticancer effects. Here, we reported a novel aromatic amide derivative SY-65 co-targeted tubulin and histone deacetylase 1 with potent Anticancer activity in vitro and in vivo. Compound SY-65 was identified as a dual inhibitor of tubulin/HDAC1 (IC50 = 3.64 and 0.529 μM, respectively) with excellent antiproliferative activity against MGC-803, HCT-116, KYSE-450, HGC-27, SGC-7901 and MKN-45 cells. Especially, compound SY-65 exhibited potent antiproliferative activity against MGC-803, HGC-27 and SGC-7901 cells with IC50 values <55 nM, which was better than that of Colchicine, MS-275 and SAHA. Compound SY-65 effectively inhibited tubulin polymerization and bound to the colchicine binding site of tubulin, as well as inhibited HDAC1 activity both intra/extracellularly. Molecular docking results suggested there were the well-defined binding modes of compound SY-65 in HDAC1 and tubulin. In addition, compound SY-65 inhibited colony formation, interfered with the cell cycle distribution, induced cell cycle arrest at the G2/M phase and Apoptosis in MGC-803 and HGC-27 cells. Compound SY-65 also exhibited a good tumor inhibitory effect in vivo without obvious toxicity. Therefore, compound SY-65 could be developed as a novel tubulin/HDAC1 candidate inhibitor for future Cancer therapeutics.

Keywords

Anticancer activity; Epigenetic regulation; HDAC; Tubulin.

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