A detailed study of fostriecin, a potent and efficacious antitumor agent that inhibits the mitotic entry checkpoint through the selective inhibition of protein phosphatases 2A and 4, and related naturally-occurring and synthetic inhibitors of protein phosphatases (PP) will be conducted. This will include the implementation of an improved second-generation total synthesis of fostriecin, the total synthesis and stereochemical assignment of cytostatin, and the total synthesis and stereochemical assignment of sultriecin. Extensions of the studies to the definition of the fostriecin pharmacophore responsible for its potent and selective PP inhibition and the preparation of more stable and structurally simpler analogues that address issues currently limiting the clinical potential of fostriecin will be pursued.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093456-03
Application #
6686020
Study Section
Special Emphasis Panel (ZRG1-SSS-B (01))
Program Officer
Lees, Robert G
Project Start
2001-12-14
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
3
Fiscal Year
2004
Total Cost
$370,863
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Lawhorn, Brian G; Boga, Sobhana B; Wolkenberg, Scott E et al. (2006) Total synthesis and evaluation of cytostatin, its C10-C11 diastereomers, and additional key analogues: impact on PP2A inhibition. J Am Chem Soc 128:16720-32
Buck, Suzanne B; Hardouin, Christophe; Ichikawa, Satoshi et al. (2003) Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition. J Am Chem Soc 125:15694-5
Lewy, D S; Gauss, C-M; Soenen, D R et al. (2002) Fostriecin: chemistry and biology. Curr Med Chem 9:2005-32