4-benzimidazolyl-3-phenylbutanoic acids as novel PIF-pocket-targeting allosteric inhibitors of protein kinase PKCζ.
J Med Chem
; 54(19): 6714-23, 2011 Oct 13.
Article
em En
| MEDLINE
| ID: mdl-21863889
ABSTRACT
Protein kinase inhibitors with an allosteric mode of action are expected to reach, in many cases, higher selectivity for the target enzyme than ATP-competitive compounds. Therefore, basic research is aiming at identifying and establishing novel sites on the catalytic domain of protein kinases which might be targeted by allosteric inhibitors. We previously published the first structure-activity relationships (SARs) for allosteric activators of protein kinase PDK1. Here, we present the design, synthesis, and SAR data on a series of novel compounds, 4-benzimidazolyl-3-phenylbutanoic acids, that inhibit the atypical protein kinace C (PKC) ζ via binding to the PIF-pocket. Key positions were identified in the compounds that can be modified to increase potency and selectivity. Some congeners showed a high selectivity toward PKCζ, lacking inhibition of the most closely related isoform, PKCι, and of further AGC kinases. Furthermore, evidence is provided that these compounds are also active toward cellular PKCζ without loss of potency compared to the cell-free assay.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Quinase C
/
Butiratos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article