Definition

An orally bioavailable inhibitor of two proteins that are part of the corepressor to the silencer repressor element 1 (RE1) silencing transcription factor (REST) complex (CoREST complex): histone deacetylase (HDAC) type 6 (HDAC6; HDAC-6) and lysine-specific demethylase 1 (LSD1; KDM1A), with potential antineoplastic activity. Upon oral administration, LSD1/HDAC6 inhibitor JBI-802 targets, binds to and inhibits the activity of HDAC6, and prevents the HDAC6-mediated aggresomal degradation of ubiquitinated proteins. This results in an accumulation of highly acetylated chromatin histones, the induction of chromatin remodeling and an altered pattern of gene expression. This results in a selective transcription of tumor suppressor genes, tumor suppressor protein-mediated inhibition of tumor cell division and an induction of apoptosis in tumor cells that overexpress HDAC6. It also modulates genes involved in immune suppression. In addition, JBI-802 specifically targets, binds to and inhibits LSD1, a demethylase that suppresses the expression of target genes by converting the di- and mono-methylated forms of lysine at position 4 of histone 3 (H3K4) to mono- and unmethylated H3K4, respectively. LSD1 inhibition enhances H3K4 methylation and increases the expression of tumor suppressor genes. This may lead to an inhibition of cell growth in LSD1-overexpressing tumor cells. In addition, LSD1 demethylates mono- or di-methylated H3K9 which increases gene expression of tumor promoting genes; inhibition of LSD1 promotes H3K9 methylation and decreases transcription of these genes. HDAC6, which is upregulated in many tumor cell types, deacetylates chromatin histone proteins. LSD1 is overexpressed in a number of tumor cell types. LSD1 acts on histone H3 as a transcription co-repressor through demethylation of lysine 4 (H3K4) or as a transcription co-activator through demethylation of lysine 9 (H3K9).