The long-range goal of the research is to discover novel, water soluble geldanamycin analogs useful in cancer chemotherapy. 17-Allyamino-17- demethoxygeldanamycin (17-AAG) is in clinical trials. To overcome important shortcomings of this drug, we will seek drugs related to 17- AAG that are water soluble and exhibit potent cytostatic or cytotoxic effects on specific types of tumor cells representing cancers caused by aberrant protein kinase mediated signalling involving Hsp90. This will be achieved by selectivity altering the structure of geldanamycin and the 17-AAG made from it through manipulation of the polyketide synthase genes for geldanamycin biosynthesis to both introduce and remove functionality to enhance water solubility and anti-tumor activity. Scaffolds made in this way will be converted by chemical methods to the desired C17-substituted analogs, and their biological activity will be evaluated by determining relative binding affinity to Hsp90 and the amount of depletion of the level of an HSP90-dependent protein kinase. Analogs with <1 micromolar activity will then be tested in vitro against a panel of tumor cell lines known to respond to Hsp inhibitors to identify lead drugs for pre-clinical development.
Successful use of the genetic engineering approach to make noel microbial metabolites related to geldanamycin and 17-allyamino-17- demethoxygeldanamycin will result in new 17-substituted geldanamycin analogs that can be developed into cancer chemotherapy drugs by Kosan Biosciences or other pharmaceutical firms.
| Patel, Kedar; Piagentini, Misty; Rascher, Andreas et al. (2004) Engineered biosynthesis of geldanamycin analogs for Hsp90 inhibition. Chem Biol 11:1625-33 |
| Rascher, Andreas; Hu, Zhihao; Viswanathan, Nina et al. (2003) Cloning and characterization of a gene cluster for geldanamycin production in Streptomyces hygroscopicus NRRL 3602. FEMS Microbiol Lett 218:223-30 |
