Engineered biosynthesis of geldanamycin analogs for Hsp90 inhibition.
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.
Patel
Kedar
K
Kosan Biosciences, Inc., Hayward, CA 94545, USA.
Piagentini
Misty
M
Rascher
Andreas
A
Tian
Zong-Qiang
ZQ
Buchanan
Greg O
GO
Regentin
Rika
R
Hu
Zhihao
Z
Hutchinson
C R
CR
McDaniel
Robert
R
D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D015964:Gene Expression Regulation, Bacterial; D005818:Genetic Engineering; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D048630:Polyketide Synthases / Q000235:genetics* / Q000378:metabolism; D011809:Quinones / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D048630:Polyketide Synthases; C001277:geldanamycin