Screening for Small-Molecule Inhibitors of Histone Methyltransferases.
Epigenetic drug
HMT
Histone methyltransferase
Hit triage
Small molecule inhibitor
Journal
Methods in molecular biology (Clifton, N.J.)
ISSN: 1940-6029
Titre abrégé: Methods Mol Biol
Pays: United States
ID NLM: 9214969
Informations de publication
Date de publication:
2022
2022
Historique:
entrez:
22
6
2022
pubmed:
23
6
2022
medline:
25
6
2022
Statut:
ppublish
Résumé
Potent and highly selective small-molecule inhibitors are needed to unravel the biological complexities of histone methyltransferases and to reveal their therapeutic potential. A prerequisite to developing these inhibitors is the identification of validated chemical matter for initiating a medicinal chemistry campaign. For the most part, finding these initial starting points occurs through screening of large, unbiased compound libraries. The size and nature of these libraries, coupled with the complexities of the bisubstrate utilizing histone methyltransferases, necessitates that the primary screen and subsequent hit triage be carefully considered.In this chapter, using EZH2 as a representative example, we describe a screening and hit triage campaign that identified validated chemical matter allowing initiation of medicinal chemistry studies. Moreover, we discuss a cell-based assay to support lead identification and optimization. The approach described here entailing a mixture of biochemical, biophysical and cell-based assays should be applicable to identifying validated starting points for other histone methyltransferases.
Identifiants
pubmed: 35733027
doi: 10.1007/978-1-0716-2481-4_20
doi:
Substances chimiques
Enzyme Inhibitors
0
Histone Methyltransferases
EC 2.1.1.-
Methyltransferases
EC 2.1.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
477-490Informations de copyright
© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.
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