Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A(2).
Bioorg Med Chem Lett
; 23(3): 839-43, 2013 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-23260346
ABSTRACT
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2) or PLA(2)G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids. Lp-PLA(2) has also been implicated as a pro-tumorigenic enzyme in human prostate cancer. Several inhibitors of Lp-PLA(2) have been described, including darapladib, which is currently in phase 3 clinical development for the treatment of atherosclerosis. The selectivity that darapladib and other Lp-PLA(2) inhibitors display across the larger serine hydrolase family has not, however, been reported. Here, we describe the use of both general and tailored activity-based probes for profiling Lp-PLA(2) and inhibitors of this enzyme in native biological systems. We show that both darapladib and a novel class of structurally distinct carbamate inhibitors inactivate Lp-PLA(2) in mouse tissues and human cell lines with high selectivity. Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA(2) function in biological systems.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Quinolinas
/
1-Alquil-2-acetilglicerofosfocolina Esterase
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos