2. Academic Validation
  3. Discovery of natural product-like spirooxindole derivatives as highly potent and selective LSD1/KDM1A inhibitors for AML treatment

Discovery of natural product-like spirooxindole derivatives as highly potent and selective LSD1/KDM1A inhibitors for AML treatment

  • Bioorg Chem. 2022 Mar;120:105596. doi: 10.1016/j.bioorg.2022.105596.
Chao Yang 1,  Yuan Fang 2,  Xiang Luo 2,  Dehong Teng 1,  Zhongqiu Liu 2,  Yingtang Zhou 3,  Guochao Liao 4
Affiliations

Affiliations

  • 1 National Engineering Research Center for Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University, Zhoushan, Zhejiang Province 316022, China.
  • 2 Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 3 National Engineering Research Center for Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University, Zhoushan, Zhejiang Province 316022, China. Electronic address: zhouyingtang@zjou.edu.cn.
  • 4 Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. Electronic address: liao@gzucm.edu.cn.
PMID: 35051709 DOI: 10.1016/j.bioorg.2022.105596
Abstract

Histone lysine specific demethylase 1 (LSD1) is a promising new therapeutic target for Cancer therapy. Following the work on the discovery of natural LSD1 inhibitor higenamine, we herein performed further structure-based design, synthesis, and extensive structure-activity relationship (SAR) studies, affording structurally new spirooxindole derivatives. Particularly, FY-56 was identified to be a highly potent LSD1 inhibitor (IC50 = 42 nM) and showed high selectivity over monoamine oxidases (MAO-A/B). Mechanistic studies showed that FY-56 moderately inhibited the proliferation and clone formation of leukemia cells, induced H3K4me1/2 accumulation and p53 activation as well as reduced the mRNA levels of the transcription factors HOXA9 and MEIS1. Meanwhile, FY-56 induced differentiation of MOLM-13 and MV4-11 cells, accompanied by an enhanced percentage of markers characteristic to differentiated macrophages and monocytes. Further in vivo studies showed that FY-56 obviously reduced the proportion of CD45+/CD33+ leukocytes in peripheral blood and spleen, and significantly prolonged the survival rate of mice. Collectively, FY-56 represents a structurally novel, highly potent and selective LSD1 inhibitor and exhibits therapeutic promise for AML treatment. The spirooxindole scaffold derived from FY-56 could be used to design structurally new LSD1 inhibitors for treating human diseases.

Keywords

AML treatment; Histone demethylase; LSD1 inhibitor; Natural product; Spirooxindole.

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