LSD1 (lysine specific demethylase I), a flavin-dependent histone demethylase that oxidatively removes methyl groups from mono- and di-methylated Lys-4 of histone H3 (H3K4), is a component of various transcriptional corepressor complexes that often include HDAC1/2 and CoREST. LSD1 is a key regulator of the epigenome, modulating gene transcription at both histone and DNA levels, making it an interesting target in oncology. High-throughput screening of the GSK compound collection led to the identification of validated hits based on tranylcypromine (Parnate�), a known irreversible LSD1 inhibitor. Lead optimization, with a focus on physicochemical properties, produced highly potent, selective, mechanism-based inhibitors of LSD1 with good oral bioavailability.

Mechanism-based irreversible inhibitors of the lysine demethylase LSD1

246th National Meeting (2013)

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