Engineered Biosynthesis of Geldanamycin Analogs for Hsp90 Inhibition

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.

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

“…In a more recent study, a conserved hydrophobic motif in HSP90 β strand has been reported to regulate the secretion and function of HSP90 (30). Thus, the presence of detergent can influence 17AAG binding to HSP90, potentially contributing to the poor correlation between binding affinity and cytotoxicity (31,32) or to the potency gap between biochemical binding and Her2 degradation (33). We tested detergent by itself and found that 17AAG can significantly bind to detergent micelles.…”

A New Post-PKS Modification Process in the Carbamoyltransferase Gene Inactivation Strain of Streptomyces hygroscopicus 17997

“…geldanus NRRL 3602 [15]. The genetic manipulation of the gene or domain of the GDM biosynthetic gene cluster is helpful for understanding the biosynthesis process, and creates new analogues of GDM [16,18].…”

Hutchinson's legacy: keeping on polyketide biosynthesis

“…79,80 Other geldanamycin analogs with improved therapeutic properties have been developed by Professor Hutchinson and collaborators by engineering its biosynthesis gene cluster. 81,82 We planned to generate novel streptolydigin derivatives, using combinatorial biosynthetic approaches, in an attempt to obtain better cytotoxic or antibiotic compounds. Structurally, streptolydigin is a polyketide/non-ribosomal peptide that belongs to the tetramic acids family.…”