New Potent DOT1L Inhibitors for
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:
12 Dec 2019
12 Dec 2019
Historique:
received:
01
10
2019
accepted:
25
11
2019
entrez:
21
12
2019
pubmed:
21
12
2019
medline:
21
12
2019
Statut:
epublish
Résumé
In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.
Identifiants
pubmed: 31857842
doi: 10.1021/acsmedchemlett.9b00452
pmc: PMC6912874
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1655-1660Informations de copyright
Copyright © 2019 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare the following competing financial interest(s): Authors are shareholders of Novartis and/or employees of Novartis.
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