SBIR-STTR Award

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. PROPOSED COMMERCIAL APPLICATIONS: 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.

Thesaurus Terms:
antineoplastic antibiotic, drug design /synthesis /production, drug discovery /isolation, quinone, water solubility chemical structure, heat shock protein, protein kinase chemical synthesis

The long-range goal of our research program is to discover novel, more potent water soluble geldanamycin analogs and to develop one of them into a useful antitumor drug. 17-Allylamino-17-desmethoxygeldanamycin (17-AAG), the first Hsp90 inhibitor to enter Phase I clinical trials for cancer chemotherapy, has shown higher blood levels and lesser liver toxicity than geldanamycin. We will seek compounds related to 17-AAG and its more water soluble analog, 17-(2'-dimethylamino)ethylamino-17-desmethoxygeldanamycin (17-DMAG), independently discovered at Kosan Biosciences and the National Cancer Institute. In Phase II research, we aim to discover analogs with satisfactory watersolubility that have better pharmacokinetics and pharmacodynamics, and greater potency or lesser unwanted toxicity than either of these drugs. This will be achieved by selectively altering the chemical structure of geldanamycin through manipulation of the geldanamycin biosynthesis genes, following successful proof-of-concept experiments carried out in our Phase I program. Microbial processes will be developed to provide end products or starting materials for synthetic modification, enabling the preparation and biological testing of "second generation" geldanamycin analogs through pursuit of the following Specific Aims. (1) Optimize the microbial process for production of the best "desmethyl, desmethoxy or hydroxygeldanamycin scaffold" discovered by PKS gene engineering in Phase I. (2) Develop microbial processes to make the following compounds: 11-O-methyl-17R-geldanamycin, 15-hydroxy-17R-geldanamycin and 21-deshydroxy-17R-geldanamycin. (3) Identify a second generation antitumor drug development candidate by synthesis of specific geldanamycin analogs and determination of the following biological properties: Binding to Hsp90, Plasma protein binding, Cellular uptake, Effect on depletion of Hsp90 client proteins, Inhibition of drug metabolizing CYP450 enzymes, Cytotoxic activity in vitro, Antitumor activity in mouse tumor model(s), Pharmacokinetics (PK), pharmacodynamics (PD) and other characteristics of absorption, distribution, metabolism and excretion (ADME) through preclinical studies carried out in vitro and in animals.. By these studies, we will identify the best geldanamycin analog to carry forward into drug development, with the eventual aim of filing and IND application and performing clinical trials.

Thesaurus Terms:
analog, antineoplastic antibiotic, drug design /synthesis /production, drug discovery /isolation, quinone chemical structure, chemical synthesis, heat shock protein, pharmacokinetics, protein kinase, water solubility