Engineered biosynthesis of geldanamycin analogs for Hsp90 inhibition.
Chem Biol
; 11(12): 1625-33, 2004 Dec.
Article
em En
| MEDLINE
| ID: mdl-15610846
ABSTRACT
Geldanamycin, a polyketide natural product, is of significant interest for development of new anticancer drugs that target the protein chaperone Hsp90. While the chemically reactive groups of geldanamycin have been exploited to make a number of synthetic analogs, including 17-allylamino-17-demethoxy geldanamycin (17-AAG), currently in clinical evaluation, the "inert" groups of the molecule remain unexplored for structure-activity relationships. We have used genetic engineering of the geldanamycin polyketide synthase (GdmPKS) gene cluster in Streptomyces hygroscopicus to modify geldanamycin at such positions. Substitutions of acyltransferase domains were made in six of the seven GdmPKS modules. Four of these led to production of 2-desmethyl, 6-desmethoxy, 8-desmethyl, and 14-desmethyl derivatives, including one analog with a four-fold enhanced affinity for Hsp90. The genetic tools developed for geldanamycin gene manipulation will be useful for engineering additional analogs that aid the development of this chemotherapeutic agent.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinonas
/
Engenharia Genética
/
Proteínas de Choque Térmico HSP90
/
Policetídeo Sintases
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Chem Biol
Assunto da revista:
BIOLOGIA
/
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos