Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 23, Pages 9496-9508Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm400870h
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Funding
- Huntsman Cancer Foundation
- National Cancer Institute of the National Institutes of Health [P30CA042014]
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Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is an attractive therapeutic target in multiple malignancies. Here we report a structure-based virtual screen of a compound library containing similar to 2 million small molecular entities. Computational docking and scoring followed by biochemical screening led to the identification of a novel N'-(1-phenylethylidene)-benzohydrazide series of LSD1 inhibitors with hits showing biochemical IC(50)s in the 200-400 nM range. Hit-to-lead optimization and structure activity relationship studies aided in the discovery of compound 12, with a K-i of 31 nM. Compound 12 is reversible and specific for LSD1 as compared to the monoamine oxidases shows minimal inhibition of CYPs and hERG and inhibits proliferation and survival in several cancer cell lines, including breast and colorectal cancer. Compound 12 may be used to probe LSD1's biological role in these cancers.
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