Brain-Penetrant LSD1 Inhibitors Can Block Memory Consolidation

Abstract

Modulation of histone modifications in the brain may represent a new mechanism for brain disorder therapy. Post-translational modifications of histones regulate gene expression, affecting major cellular processes such as proliferation, differentiation, and function. An important enzyme involved in one of these histone modifications is lysine specific demethylase 1 (LSD1). This enzyme is flavin-dependent and exhibits homology to amine oxidases. Parnate (2-phenylcyclopropylamine (2-PCPA); tranylcypromine) is a potent inhibitor of monoamine oxidases and derivatives of 2-PCPA have been used for development of selective LSD1 inhibitors based on the ability to form covalent adducts with flavin adenine dinucleotide (FAD). Here we report the synthesis and in vitro characterization of LSD1 inhibitors that bond covalently to FAD. The two most potent and selective inhibitors were used to demonstrate brain penetration when administered systemically to rodents. First, radiosynthesis of a positron-emitting analog was used to obtain preliminary bio-distribution data and whole brain time-activity curves. Second, we demonstrate that this series of LSD1 inhibitors is capable of producing a cognitive effect in a mouse model. By using a memory formation paradigm, novel object recognition, we show that LSD1 inhibition can abolish long-term memory formation without affecting short-term memory, providing further evidence for the importance of reversible histone methylation in the function of the nervous system.

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

“…30 RN-1 has been reported to affect long-term memory in mice and, therefore, this may be an additional possible adverse effect of the drug. 46 Our results show that the LSD1 inhibitor RN-1 induces high levels of HbF in baboons and are consistent with previous studies showing that LSD1 plays a critical role in γ-globin silencing as a component of the DRED complex. 25,31 However, the possibility of a role for perturbation of erythroid differentiation in the mechanism of HbF reactivation cannot be excluded, and the in vivo mechanism of action will be investigated in future studies.…”

The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice

“…Higher doses (10 mg/g) of RN-1 yielded significantly more robust therapeutic effects than the lower dosage examined here (3 mg/g) in SCD mice, possibly because the higher dose regimen results in a serum concentration that is twofold higher than the IC 50, whereas the serum concentration at the lower dose regimen is below the IC 50 . 32 These findings provide ample evidence for the hematologic and physiologic benefits of interfering with LSD1 by administration of RN-1 in SCD mice and clearly indicates that RN-1 or its derivatives might be effective in the treatment of SCD as novel HbF-inducing agents.…”

“…32 We therefore investigated the in vivo effects of RN-1 on g-globin gene expression and erythroid physiology in a transgenic mouse model of SCD. 33 These SCD mice express human a-and sickle b s -globin, and therefore mimic many of the genetic, hematologic, and pathophysiologic features that are found in human SCD patients, including irreversibly sickled RBCs, hemolytic anemia, high reticulocyte count, hepatosplenomegaly, and other organ pathology.…”

Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties

“…This observation is consistent with reported brain-related effects of LSD1 inhibition. 29 Our results indicate that compounds 6a, 6b, 9a and 9c possess biological activity related to the mechanisms involved in cell viability. The data from in vitro LSD1 inhibition are consistent with compounds 6a, 6b and 9a possessing LSD1 inhibitory properties, although the IC 50 values are higher by an order of 10 4 .…”