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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44CA096262-03
Application #
6875620
Study Section
Special Emphasis Panel (ZRG1-SSS-L (10))
Program Officer
Fu, Yali
Project Start
2004-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$375,000
Indirect Cost
Name
Kosan Biosciences, Inc.
Department
Type
DUNS #
932981319
City
Hayward
State
CA
Country
United States
Zip Code
94545
Menzella, Hugo G; Tran, Thomas-Toan; Carney, John R et al. (2009) Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus. J Med Chem 52:1518-21