Protein-ligand crystal structures can guide the design of selective inhibitors of the FGFR tyrosine kinase.
J Med Chem
; 55(11): 5003-12, 2012 Jun 14.
Article
en En
| MEDLINE
| ID: mdl-22612866
ABSTRACT
The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Pirimidinas
/
Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Reino Unido