High-throughput virtual screening identifies novel N'-(1-phenylethylidene)-benzohydrazides as potent, specific, and reversible LSD1 inhibitors.
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'-(1-phenylethylidene)-benzohydrazide series of LSD1 inhibitors with hits showing biochemical IC50s in the 200-400 nM range. Hit-to-lead optimization and structure-activity relationship studies aided in the discovery of compound 12, with a Ki 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.
Center for Investigational Therapeutics (CIT), Huntsman Cancer Institute, University of Utah , 2000 Circle of Hope, Salt Lake City, Utah 84112, United States.
Venkataswamy
V
Sorna
Emily R
ER
Theisen
Bret
B
Stephens
Steven L
SL
Warner
David J
DJ
Bearss
Hariprasad
H
Vankayalapati
Sunil
S
Sharma
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D013329:Structure-Activity Relationship
D006834:Hydrazines; D056466:Histone Demethylases; C495195:KDM1A protein, human; C006712:benzoylhydrazine