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Discovery of orally active chalcones as histone lysine specific demethylase 1 inhibitors for the treatment of leukaemia.

Authors
  • Li, Yang1
  • Sun, Ying1
  • Zhou, Yang1
  • Li, Xinyang1
  • Zhang, Huan1
  • Zhang, Guojun1
  • 1 Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China. , (China)
Type
Published Article
Journal
Journal of Enzyme Inhibition and Medicinal Chemistry
Publisher
Informa UK (Taylor & Francis)
Publication Date
Dec 01, 2021
Volume
36
Issue
1
Pages
207–217
Identifiers
DOI: 10.1080/14756366.2020.1852556
PMID: 33307878
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Histone lysine specific demethylase 1 (LSD1) has emerged as an attractive molecule target for the discovery of potently anticancer drugs to treat leukaemia. In this study, a series of novel chalcone derivatives were designed, synthesised and evaluated for their inhibitory activities against LSD1 in vitro. Among all these compounds, D6 displayed the best LSD1 inhibitory activity with an IC50 value of 0.14 μM. In the cellular level, compound D6 can induce the accumulation of H3K9me1/2 and inhibit cell proliferation by inactivating LSD1. It exhibited the potent antiproliferative activity with IC50 values of 1.10 μM, 3.64 μM, 3.85 μM, 1.87 μM, 0.87 μM and 2.73 μM against HAL-01, KE-37, P30-OHK, SUP-B15, MOLT-4 and LC4-1 cells, respectively. Importantly, compound D6 significantly suppressed MOLT-4 xenograft tumour growth in vivo, indicating its great potential as an orally bioavailable candidate for leukaemia therapy.

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