2. Academic Validation
  3. Discovery of new tetrahydroisoquinolines as potent and selective LSD1 inhibitors for the treatment of MLL-rearranged leukemia

Discovery of new tetrahydroisoquinolines as potent and selective LSD1 inhibitors for the treatment of MLL-rearranged leukemia

  • Eur J Med Chem. 2023 Sep 5;257:115516. doi: 10.1016/j.ejmech.2023.115516.
Chao Yang 1,  Yuan Fang 2,  Yaxuan Hu 1,  Tiantian Tian 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 Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, Guangdong, 519087, China. Electronic address: [email protected].
  • 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: [email protected].
PMID: 37257211 DOI: 10.1016/j.ejmech.2023.115516
Abstract

Histone lysine-specific demethylase 1 (LSD1) is a promising target for Cancer therapy. Here, we performed the design, synthesis, and extensive structure-activity relationship (SAR) studies based on our previously discovered natural LSD1 inhibitor, higenamine. We found that the tetracyclic tetrahydroisoquinoline FY-21 is a potent and selective inhibitor of LSD1 (IC50 = 340 nM). FY-21 inhibited leukemia cell proliferation and colony formation and increased the level of p53 expression. Meanwhile, FY-21 reduced the mRNA levels of the transcription factors HOXA9 and MEIS1. Furthermore, FY-21 significantly induced leukemia cell differentiation. In vivo studies showed that FY-21 prolonged the survival rate of leukemia mice. Collectively, FY-21 is a potent, selective LSD1 inhibitor and can serve as a lead compound for the development of novel and highly effective LSD1 inhibitors for AML treatment.

Keywords

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

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