Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating β-Thalassemia and Sickle Cell Disease.
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:
14 Jan 2021
14 Jan 2021
Historique:
received:
28
10
2020
accepted:
21
12
2020
entrez:
25
1
2021
pubmed:
26
1
2021
medline:
26
1
2021
Statut:
epublish
Résumé
Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating β-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating β-thalassemia and sickle cell disease.
Identifiants
pubmed: 33488973
doi: 10.1021/acsmedchemlett.0c00572
pmc: PMC7812670
doi:
Types de publication
Journal Article
Langues
eng
Pagination
121-128Informations de copyright
© 2020 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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