2. Academic Validation
  3. Discovery of novel tranylcypromine-indazole-based derivatives as LSD1 inhibitors for acute myeloid leukemia treatment

Discovery of novel tranylcypromine-indazole-based derivatives as LSD1 inhibitors for acute myeloid leukemia treatment

  • Eur J Med Chem. 2025 May 5:289:117438. doi: 10.1016/j.ejmech.2025.117438.
Ming-Jie Huang 1,  Qiuge Liu 2,  Jian Song 2,  Beiling Gao 3,  Saiyang Zhang 4,  Lihua Huang 5
Affiliations

Affiliations

  • 1 College of Chemistry, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
  • 2 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
  • 3 College of Chemistry, Zhengzhou University, Zhengzhou, Henan, 450001, PR China. Electronic address: gaobeiling@zzu.edu.cn.
  • 4 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, PR China. Electronic address: saiyangz@zzu.edu.cn.
  • 5 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Henan International Joint Laboratory of Tumor Theranostical Cluster Materials, College of Chemistry, Zhengzhou University, Zhengzhou, Henan, 450001, PR China. Electronic address: hlh606@zzu.edu.cn.
PMID: 40022881 DOI: 10.1016/j.ejmech.2025.117438
Abstract

As an epigenetic enzyme, Lysine-specific demethylase (LSD1) has emerged as a promising target for Cancer therapy. Based on the structure of tranylcypromine indazole, a series of LSD1 inhibitors have been designed and synthesized in this work. Most compounds have excellent inhibitory activity against LSD1. The representative compound, 9e, proved to be a highly effective LSD1 inhibitor, with an IC50 value of 9.85 nM, and demonstrated exceptional selectivity for LSD1 over both MAOs and hERG. Meanwhile, compound 9e exhibited significant inhibitory activity against leukemia cells, especially MV-4-11, HL-60, and THP-1 cells, with IC50 values of 1.40, 1.54, and 1.96 μM respectively. Additional biological mechanisms suggested that compound 9e could directly target LSD1 and inhibit LSD1 in MV-4-11 cells, resulting in a significant increase in the expression levels of H3K4me1/2. In addition, compound 9e was found to induce Apoptosis and upregulate of CD86-expression in MV-4-11 cells. All these findings indicated that compound 9e, a tranylcypromine-indazole derivative, provided a structural basis for LSD1 inhibitors in the treatment of acute myeloid leukemia.

Keywords

Activities; Acute myeloid leukemia; LSD1; Tranylcypromine-indazole.

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