ORY-2001

ORY-2001 is a covalent inhibitor of lysine-specific demethylase 1 (LSD1) and monoamine oxidase B (MAO-B; IC₅₀s = 0.101 and 0.073 µM, respectively).¹ It is selective for LSD1 and MAO-B over MAO-A (IC₅₀ = 5.47 µM) and LSD2, spermine oxidase (SMOX), and L-amino acid oxidase (LAAO) at 10 µM, as well as a panel of 19 additional epigenetic targets and a panel of 92 receptors, ion channels, enzymes, and transporters at 10 µM. ORY-2001 induces differentiation in THP-1 acute myeloid leukemia (AML) cells (EC₅₀ = 21 nM). In vivo, ORY-2001 (0.11-3.2 mg/kg) reverses memory deficits in the SAMP8 mouse model of accelerated aging and Alzheimer’s disease. It also reduces aggression in SAMP8 mice when administered at a dose of 0.96 mg/kg. ORY-2001 (0.05-1 mg/kg) decreases disease severity in a mouse model of experimental autoimmune encephalomyelitis (EAE).²

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1. Maes, T., Mascaró, C., Rotllant, D., et al. Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations. PLoS One 15(5), e0233468 (2020).

2. Cavalcanti, F., Gonzalez-Rey, E., Delgado, M., et al. Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis. Pharmaceutics 14(7), 1420 (2022).