Transformation of the Non-Selective Aminocyclohexanol-Based Hsp90 Inhibitor into a Grp94-Seletive Scaffold.
ACS Chem Biol
; 12(1): 244-253, 2017 01 20.
Article
em En
| MEDLINE
| ID: mdl-27959508
ABSTRACT
Glucose regulated protein 94 kDa, Grp94, is the endoplasmic reticulum (ER) localized isoform of heat shock protein 90 (Hsp90) that is responsible for the trafficking and maturation of toll-like receptors, immunoglobulins, and integrins. As a result, Grp94 has emerged as a therapeutic target to disrupt cellular communication, adhesion, and tumor proliferation, potentially with fewer side effects compared to pan-inhibitors of all Hsp90 isoforms. Although, the N-terminal ATP binding site is highly conserved among all four Hsp90 isoforms, recent cocrystal structures of Grp94 have revealed subtle differences between Grp94 and other Hsp90 isoforms that has been exploited for the development of Grp94-selective inhibitors. In the current study, a structure-based approach has been applied to a Grp94 nonselective compound, SNX 2112, which led to the development of 8j (ACO1), a Grp94-selective inhibitor that manifests â¼440 nM affinity and >200-fold selectivity against cytosolic Hsp90 isoforms.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
/
Proteínas de Choque Térmico HSP90
/
Ortoaminobenzoatos
Limite:
Humans
Idioma:
En
Revista:
ACS Chem Biol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos