A Dual Inhibitor of DYRK1A and GSK3ß for ß-Cell Proliferation: Aminopyrazine Derivative GNF4877.
ChemMedChem
; 15(16): 1562-1570, 2020 08 19.
Article
em En
| MEDLINE
| ID: mdl-32613743
ABSTRACT
Loss of ß-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase ß-cell mass are less developed. Promoting ß-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring ß-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3ß (GSK3ß) was previously reported to induce primary human ß-cell proliferation inâ
vitro and inâ
vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring ß-cell proliferation.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
/
Proteínas Serina-Treonina Quinases
/
Inibidores de Proteínas Quinases
/
Células Secretoras de Insulina
/
Glicogênio Sintase Quinase 3 beta
Limite:
Animals
/
Humans
Idioma:
En
Revista:
ChemMedChem
Assunto da revista:
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos