Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
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Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: UMLS:C0268596 (
EMA
)
2,520
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 H
3
receptor (H
3
R) 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 H
3
R 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 H
3
R 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.
...
PMID:Epigenetics meets GPCR: inhibition of histone H3 methyltransferase (G9a) and histamine H
3
receptor for Prader-Willi Syndrome. 3278 17
