RN-1 (hydrochloride)

RN-1 (hydrochloride) is a brain-penetrant, potent and irreversible LSD1 inhibitor with IC50 values of 10-70 nM [1].

Lysine-specific demethylase 1 (LSD1) is a flavin-dependent monoamine oxidase that demethylate mono- and di-methylated lysines, specifically histone 3, lysines 4 and 9 (H3K4 and H3K9) [2].

RN-1 (hydrochloride) is a potent and irreversible LSD1 inhibitor with IC50 values of 10-70 nM. However, RN-1 is much less effective against MAO-A and MAO-B with IC50 values of 0.51 and 2.785 μM, respectively [1]. In ovarian cancer lines, RN-1 also induced cytotoxicity, which was correlated with the LSD1 inhibitory potential [3].

Following intraperitoneal administration in mice, RN-1 penetrated the blood-brain barrier and the brain/plasma exposure ratio was 88.9. In mice, RN-1 significantly impaired long-term memory but not short-term memory. And long-term memory impairment was due to a brain-specific effect [1]. In a sickle cell disease (SCD) mouse model, RN-1 induced HbF synthesis and increased frequencies of HbF-positive cells and mature erythrocytes, as well as reduced reticulocytes and sickle cells. And the RN-1 treated mice did not exhibit the necrotic lesions in the liver and spleen [4].

References:
[1].  Neelamegam R, Ricq EL, Malvaez M, et al. Brain-penetrant LSD1 inhibitors can block memory consolidation. ACS Chem Neurosci. 2012 Feb 15;3(2):120-128.
[2].  Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004 Dec 29;119(7):941-53.
[3].  Konovalov S, Garcia-Bassets I. Analysis of the levels of lysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines. J Ovarian Res. 2013 Oct 29;6(1):75.
[4].  Cui S, Lim KC, Shi L, et al. The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice. Blood. 2015 Jul 16;126(3):386-96.