2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel dual inhibitors targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDAC) for treatment of gastric cancer

Design, synthesis, and biological evaluation of novel dual inhibitors targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDAC) for treatment of gastric cancer

  • Eur J Med Chem. 2021 Aug 5:220:113453. doi: 10.1016/j.ejmech.2021.113453.
Ying-Chao Duan 1,  Lin-Feng Jin 2,  Hong-Mei Ren 3,  Shao-Jie Zhang 2,  Yue-Jiao Liu 3,  Yong-Tao Xu 4,  Zi-Hao He 5,  Yu Song 2,  Hang Yuan 2,  Shu-Hui Chen 2,  Yuan-Yuan Guan 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, 453003, China. Electronic address: duanyingchao1986@163.com.
  • 2 School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
  • 3 Key Lab of Advanced Drug Preparation Technologies, Ministry of Education of China, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
  • 4 School of Medical Engineering, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
  • 5 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, ChaoYang District, Beijing, 100029, China.
  • 6 School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, 453003, China. Electronic address: 131011@xxmu.edu.cn.
PMID: 33957387 DOI: 10.1016/j.ejmech.2021.113453
Abstract

LSD1 and HDAC are physical and functional related to each Other in various human cancers and simultaneous pharmacological inhibition of LSD1 and HDAC exerts synergistic anti-cancer effects. In this work, a series of novel LSD1/HDAC bifunctional inhibitors with a styrylpyridine skeleton were designed and synthesized based on our previously reported LSD1 inhibitors. The representative compounds 5d and 5m showed potent activity against LSD1 and HDAC at both molecular and cellular level and displayed high selectivity against MAO-A/B. Moreover, compounds 5d and 5m demonstrated potent antiproliferative activities against MGC-803 and HCT-116 Cancer cell lines. Notably, compound 5m showed superior in vitro Anticancer potency against a panel of gastric Cancer cell lines than ORY-1001 and SP-2509 with IC50 values ranging from 0.23 to 1.56 μM. Compounds 5d and 5m significantly modulated the expression of Bcl-2, Bax, Vimentin, ZO-1 and E-cadherin, induced Apoptosis, reduced colony formation and suppressed migration in MGC-803 Cancer cells. In addition, preliminary absorption, distribution, metabolism, excretion (ADME) studies revealed that compounds 5d and 5m showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). Those results indicated that compound 5m could be a promising lead compound for further development as a therapeutic agent in gastric cancers via LSD1 and HDAC dual inhibition.

Keywords

Anticancer; Dual inhibitor; HDAC; LSD1.

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