Cell division cycle 25 (cdc25) is a dual specific protein tyrosine phosphatase (dsPTPase) involved in the regulation of cyclin-dependent kinases (CDKs), which in turn regulate progression through the cell cycle by mediating checkpoint responses in cells with DNA damage. Recently, cdc25 has been shown to play a role in cancer. Overexpression of cdc25 has been observed in human tumor cells such as head and neck squamous carcinomas, lymphomas, gastric carcinomas, non-small cell lung cancer, kidney, and ovarian cancer cells. The implication of cdc25 in cell transformation and tumorigenesis makes it an attractive target for drug discovery and intervention of oncogenesis. cdc25 target-specific screening assay using the principle of drug-induced haploinsufficiency will be carried out with using Saccharomyces cerevisiae heterozygous diploid cdc25 deletion strain. Pair-wise comparisons of growth of yeast strains will be used to detect cdc25 inhibitors.

Marine invertebrates express a fantastic array of chemo-diverse natural products with antitumor properties, including Yondelis (ET743) from the Caribbean tunicate Ecteinascidia turbinata, which was approved in Europe in October 2007 for treatment of liposarcoma. To date, only a single marine natural product, dysidiolide from the Caribbean sponge Dysidea etheria, has been identified as an inhibitor of cdc25 (IC50 = 9.4 uM). Compound 1 inhibits growth of A-549 human lung carcinoma (IC50 = 4.7 uM) and P388 murine leukemia cells (IC50 = 1.5 uM) and has been further evaluated at the Memorial Sloan-Kettering Cancer Center. Our objective is the discovery of nanomolar (nM) inhibitors of cdc25, from a collection (up to N=100) of rare cryptic sponges, most of which only grow as thin veneers on coral substrates, walls and surfaces shaded from light. Poor understanding of their chemistry is a consequence of their rarity, ephemeral life-cycle and low-mass yields, however our preliminary results suggest they have high bioactivity. Consequently, they represent potential novel sources of new natural products. New NMR instrumentation (600 MHz 1.7 mm microprobe) that became available at UCSD in August, 2007 revolutionizes our ability to elucidate molecular structures of rare natural products isolated in only nanomole (nmol) quantities. Active compounds will be purified by bioassay-guided pre-fractionation, mass-dependent separation methods, including hydrophobic gel permeation chromatography, HPLC and final their structure elucidation completed by mass spectrometry and 600 MHz microprobe NMR studies at the Skaggs School of Pharmacy and Pharmaceutical Science. Lead compounds will be selected for synthesis and evaluated for their antitumor potential in CML and prostate cancer in collaboration with investigators at the UCSD Moores Cancer Center (Dennis Carson, Wolf Wrasidlo, Catriona Jamieson).

PUBLICATIONS (resulting from this training)

Information pending - trainee just commenced training