Histone demethylases such as lysine-specific demethylase 1 (LSD1) mediate an important cellular mechanism for epigenetic control of gene expression. In particular, histone 3 dimethyl lysine 4 (H3K4me2) is a transcription activating chromatin mark at gene promoters, and aberrant demethylation of this mark by LSD1 may broadly repress the expression of a variety of genes that are important in human disease. We, and others, have conducted studies verifying that LSD1 is an exciting new therapeutic target. Our group has reported multiple LSD1 inhibitor chemotypes, including (bis)guanidines, (bis)biguanides, oligoamines, amidoximes and cyclic peptides. We have recently discovered a new class of LSD1 inhibitors, the 3,5-diamino-1,2,4-triazoles, that are potent inhibitors of recombinant human LSD1. These inhibitors significantly increase H3K4me2 levels, initiate chromatin remodeling and induce the re-expression of silenced genes. Because of their specificity for LSD1 and their relatively low toxicity, we have explored the use of these molecules in diseases other than cancer, where cytotoxicity is not a desirable endpoint. In this presentation, we will describe the synthesis and evaluation of this new series of LSD1 inhibitors, and present evidence that LSD1 inhibitor-mediated correction of aberrant gene silencing can have therapeutic potential in cardiovascular disease.

Small molecule epigenetic modulators for the treatment of cardiovascular disorders

249th National Meeting (2015)

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