A general strategy for creating "inactive-conformation" abl inhibitors.
Chem Biol
; 13(7): 779-86, 2006 Jul.
Article
en En
| MEDLINE
| ID: mdl-16873026
ABSTRACT
Kinase inhibitors that bind to the ATP cleft can be broadly classified into two groups those that bind exclusively to the ATP site with the kinase assuming a conformation otherwise conducive to phosphotransfer (type I), and those that exploit a hydrophobic site immediately adjacent to the ATP pocket made accessible by a conformational rearrangement of the activation loop (type II). To date, all type II inhibitors were discovered by using structure-activity-guided optimization strategies. Here, we describe a general pharmacophore model of type II inhibition that enables a rational "hybrid-design" approach whereby a 3-trifluoromethylbenzamide functionality is appended to four distinct type I scaffolds in order to convert them into their corresponding type II counterparts. We demonstrate that the designed compounds function as type II inhibitors by using biochemical and cellular kinase assays and by cocrystallography with Abl.
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Banco de datos:
MEDLINE
Asunto principal:
Proteínas Proto-Oncogénicas c-abl
/
Inhibidores Enzimáticos
/
Conformación Molecular
Idioma:
En
Año:
2006
Tipo del documento:
Article