A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
10 Mar 2022
10 Mar 2022
Historique:
received:
18
08
2021
accepted:
24
01
2022
entrez:
18
3
2022
pubmed:
19
3
2022
medline:
19
3
2022
Statut:
epublish
Résumé
Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S. Food and Drug Administration approval following promising clinical responses in cancer patients. However, the current array of EZH2 inhibitors have poor brain penetrance, limiting their use in patients with central nervous system malignancies, a number of which have been shown to be sensitive to EZH2 inhibition. To address this need, we have identified a chemical strategy, based on computational modeling of pyridone-containing EZH2 inhibitor scaffolds, to minimize P-glycoprotein activity, and here we report the first brain-penetrant EZH2 inhibitor, TDI-6118 (compound
Identifiants
pubmed: 35300079
doi: 10.1021/acsmedchemlett.1c00448
pmc: PMC8919293
doi:
Types de publication
Journal Article
Langues
eng
Pagination
377-387Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
© 2022 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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