Abstract
The role of epigenetic regulation is in large parts connected to cancer, but additionally, its therapeutic claim in neurological disorders has emerged. Inhibition of histone H3 lysine N-methyltransferase, especially G9a, has been recently shown to restore candidate genes from silenced parental chromosomes in the imprinting disorder Prader–Willi syndrome (PWS). In addition to this epigenetic approach, pitolisant as G-protein coupled histamine H3 receptor (H3R) antagonist has demonstrated promising therapeutic effects for Prader–Willi syndrome. To combine these pioneering principles of drug action, we aimed to identify compounds that combine both activities, guided by the pharmacophore blueprint for both targets. However, pitolisant as selective H3R inverse agonist with FDA and EMA-approval did not show the required inhibition at G9a. Pharmacological characterization of the prominent G9a inhibitor A-366, that is as well an inhibitor of the epigenetic reader protein Spindlin1, revealed its high affinity at H3R while showing subtype selectivity among subsets of the histaminergic and dopaminergic receptor families. This work moves prominent G9a ligands forward as pharmacological tools to prove for a potentially combined, symptomatic and causal, therapy in PWS by bridging the gap between drug development for G-protein coupled receptors and G9a as an epigenetic effector in a multi-targeting approach.
Highlights
Prader–Willi syndrome (PWS) is a rare neurogenetic disorder that affects approximately 1 of 15,000–30,000 newborn infants[1,2]
The function of the small nucleolar RNA expressed by SNORD116 has not been elucidated yet, though, the deletion of this cluster suggests a critical role for determining the PWS phenotype[8,9]
Time, the copy of information remains on the corresponding maternal chromosome[10]. The genes on this opposite parental chromosome are silenced by epigenetic mechanisms, such as DNA methylation or posttranslational histone modifications that lead to imprinting of the corresponding alleles
Summary
Prader–Willi syndrome (PWS) is a rare neurogenetic disorder that affects approximately 1 of 15,000–30,000 newborn infants[1,2]. The current pharmacotherapeutic interventions in PWS involve substitution of Growth Hormone that has shown to improve body composition and motoric strength. It can and should be applied before the first birthday of infants[1]. Though highly significant clinical studies for pitolisant in PWS patients are missing to date, recent patient-based case reports suggest benefits of this H3R targeting drug. It shows improved activity of patients, reduction of daytime-sleepiness as well as improvements in mental clarity and processing s peed[13,14,15]. Appropriate and causal pharmacotherapy for PWS is still demanded
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