Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.
ACS Med Chem Lett
; 12(4): 555-562, 2021 Apr 08.
Article
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| MEDLINE
| ID: mdl-33859795
ABSTRACT
Herein we report the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor ß-activated kinase 1 (TAK1). The target was subjected to a DNA-encoded chemical library (DECL) screen. After hit analysis a cluster of compounds was identified, which was based on a central pyrrole-2,4-1H-dicarboxamide scaffold, showing remarkable kinome selectivity. A scaffold-hop to the corresponding imidazole resulted in increased biochemical potency. Next, X-ray crystallography revealed a distinct binding mode compared to other TAK1 inhibitors. A benzylamide was found in a perpendicular orientation with respect to the core hinge-binding imidazole. Additionally, an unusual amide flip was observed in the kinase hinge region. Using structure-based drug design (SBDD), key substitutions at the pyrrolidine amide and the glycine resulted in a significant increase in biochemical potency.
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Bases de datos:
MEDLINE
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
ACS Med Chem Lett
Año:
2021
Tipo del documento:
Article
País de afiliación:
Países Bajos