Engineered biosynthesis of geldanamycin analogs for Hsp90 inhibition

被引:112
作者
Patel, K [1 ]
Piagentini, M [1 ]
Rascher, A [1 ]
Tian, ZQ [1 ]
Buchanan, GO [1 ]
Regentin, R [1 ]
Hu, ZH [1 ]
Hutchinson, CR [1 ]
McDaniel, R [1 ]
机构
[1] Kosan Biosci Inc, Hayward, CA 94545 USA
来源
CHEMISTRY & BIOLOGY | 2004年 / 11卷 / 12期
关键词
D O I
10.1016/j.chembiol.2004.09.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1625 / 1633
页数:9
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