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1.
Anal Biochem ; 350(2): 202-13, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16460658

RESUMO

Hsp90 encodes a ubiquitous molecular chaperone protein conserved among species which acts on multiple substrates, many of which are important cell-signaling proteins. Inhibition of Hsp90 function has been promoted as a mechanism to degrade client proteins involved in tumorigenesis and disease progression. Several assays to monitor inhibition of Hsp90 function currently exist but are limited in their use for a drug discovery campaign. Using data from the crystal structure of an initial hit compound, we have developed a fluorescence polarization assay to monitor binding of compounds to the ATP-binding site of Hsp90. This assay is very robust (Z' > 0.9) and can detect affinity of compounds with IC50s to 40 nM. We have used this assay in conjunction with cocrystal structures of small molecules to drive a structure-based design program aimed at the discovery and optimization of a novel class of potent Hsp90 inhibitors.


Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Polarização de Fluorescência/métodos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pirazóis/química , Pirazóis/farmacologia , Adenosina Trifosfatases/antagonistas & inibidores , Sítios de Ligação , Cristalografia por Raios X , Concentração Inibidora 50 , Resorcinóis/química , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade
2.
Biochem Biophys Res Commun ; 139(3): 896-902, 1986 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-2429659

RESUMO

The in vitro properties of two peptide aldehydes are described which relate to their potential use as elastase inhibitors in the treatment of emphysema. When compared with alpha 1-antitrypsin they demonstrate potential advantages in terms of potency, specificity and stability to cigarette smoke.


Assuntos
Aldeídos/uso terapêutico , Enfisema/tratamento farmacológico , Elastase Pancreática/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , alfa 1-Antitripsina/uso terapêutico , Ligação Competitiva , Fenômenos Químicos , Química , Humanos , Técnicas In Vitro , Cinética , Leucócitos/enzimologia , Fumar , alfa-Macroglobulinas/metabolismo
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