High-Throughput Virtual Screening Identifies Novel N鈥?(1-Phenylethylidene)-benzohydrazides as Potent, Specific, and Reversible LSD1 Inhibitors

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• 作者：Venkataswamy Sorna ; Emily R. Theisen ; Bret Stephens ; Steven L. Warner ; David J. Bearss ; Hariprasad Vankayalapati ; Sunil Sharma
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9496-9508
• 全文大小：558K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

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 2 million small molecular entities. Computational docking and scoring followed by biochemical screening led to the identification of a novel N鈥?(1-phenylethylidene)-benzohydrazide series of LSD1 inhibitors with hits showing biochemical IC₅₀s in the 200鈥?00 nM range. Hit-to-lead optimization and structure鈥揳ctivity 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鈥檚 biological role in these cancers.