Background: LSD1 plays a key role in maintaining the balance between hematopoietic stem cell characteristics and differentiation to mature myeloid cells. Mechanism-based inhibitors of LSD1, developed from the monoamine oxidase (MAO) inhibitor tranylcypromine, have recently entered clinical trials for acute myeloid leukaemia (AML). While the mechanism and inhibitory potential of these compounds are now well defined, the potential for effective reversible inhibitors of LSD1 as clinical agents is less clear. Methods: Starting from existing literature series, we employed rational medicinal chemistry and computational design using Cresset software to scaffold-hop into novel chemical space, while retaining activity against LSD1 in biochemical assays and by surface plasmon resonance (SPR). Selected compounds were tested in cellular assays and evaluated for their physicochemical properties in vitro and in vivo. Results: Three series of reversible LSD1 inhibitors have been designed and synthesised. These novel series demonstrate a clear pharmacophore for effective inhibition. The most active series displays KD values of &lt;10 nM by SPR, and IC50 values of &lt;300 nM in a CD86 cell assay. Compounds showed good metabolic stability in mouse hepatocytes, and despite displaying high efflux ratios were shown to be moderately bioavailable. Given the paucity of reversible and selective inhibitors of LSD1 available these compounds may be effective tools to drive further research into the use of LSD1 inhibitors as single agents, or in combination with other therapies.

Design and development of reversible inhibitors of lysine specific demethylase 1

253rd National Meeting (2017)

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