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

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.

• Authors: Chao Yang, Yuan Fang, Xiang Luo, Dehong Teng, Zhongqiu Liu, Yingtang Zhou, Guochao Liao
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 120 Pg. 105596 (03 2022) ISSN: 1090-2120 [Electronic] United States
• PMID: 35051709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Biological Products
• Enzyme Inhibitors
• Histone Demethylases

Topics

• Animals
• Biological Products (therapeutic use)
• Enzyme Inhibitors
• Histone Demethylases
• Leukemia, Myeloid, Acute (drug therapy)
• Mice
• Structure-Activity Relationship