2. Academic Validation
  3. Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors

Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors

  • Eur J Med Chem. 2023 May 5;253:115321. doi: 10.1016/j.ejmech.2023.115321.
Zhonghua Li 1,  Yong Yuan 1,  Pan Wang 1,  Zijuan Zhang 1,  Huifen Ma 1,  Yiran Sun 1,  Xiaowei Zhang 1,  Xiaofang Li 2,  Yonghui Qiao 1,  Feiyu Zhang 1,  Yunfang Su 1,  Junying Song 1,  Zhishen Xie 1,  Lixin Li 1,  Liying Ma 3,  Jinlian Ma 4,  Zhenqiang Zhang 5
Affiliations

Affiliations

  • 1 Henan Engineering Research Center for Prevention and Treatment of Major Chronic Diseases with Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
  • 2 Henan Engineering Research Center for Prevention and Treatment of Major Chronic Diseases with Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, China. Electronic address: drlxf2080@163.com.
  • 3 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: lianzi556@163.com.
  • 4 Henan Engineering Research Center for Prevention and Treatment of Major Chronic Diseases with Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, China. Electronic address: maliying@zzu.edu.cn.
  • 5 Henan Engineering Research Center for Prevention and Treatment of Major Chronic Diseases with Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China. Electronic address: zzqkyc@hactcm.edu.cn.
PMID: 37037137 DOI: 10.1016/j.ejmech.2023.115321
Abstract

Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for Cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B Enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.

Keywords

Antitumor; LSD1 inhibitor; Tranylcypromine; Triazolopyrimidine.

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