TITLE:

CONFORMATIONALLY BASED DESIGN OF ANTITUMOR AGENTS

DATE:

Friday, September 7th, 2007

TIME:

3:30 PM

LOCATION:

GMCS 214

SPEAKER:

Shelli R. McAlpine, Department of Chemistry, San Diego State University

ABSTRACT:

The sansalvamide A (San A) scaffold is a promising structure for the development of novel cancer therapeutics. We are utilizing our compounds to treat multiple drug-resistant cancers, including lung, colon, and pancreatic cancers. These cancers are typically aggressive and unresponsive to drugs. Consequently, there remains an immediate need for the development of antitumor agents that target these cancers. We have produced 7 compounds that are cytotoxic to 4 drug resistant cancer cell lines at nanomolar concentrations (as low as 33 nM), and it is our overall goal of this project to develop a novel chemotherapeutic agent based on the San A scaffold that targets lung cancer cell lines. We identify a candidate lead compound by: determining how changes in the structure of the San A scaffold alter its cytotoxic activity against colon, pancreatic, and lung cancer cell lines, and by investigating their mechanism of action.
In recent years we have optimized the San A scaffold to produce compounds that selectively target drug-resistant cancers. We have also identified the target for these compounds: Heat shock protein 90-beta (Hsp90). Hsp90 is up-regulated in lung cancer cells and inhibitors of Hsp90 show outstanding potential as a therapeutic tool for treating lung cancers. Our laboratory has shown that not only do our San A derivatives inhibit Hsp90 but they kill drug-resistant cancer cell lines ~20 times more effectively than a commonly used drug, Gemzar, and are >250 fold more effective at killing cancer cells than normal cells, thus limiting their potential side effects. Further, we have recently identified one compound that shows an average of high nanomolar potency against 8 lung cancer cell lines, and has an IC50 of 33 nM against one lung cancer cell line (HOP-92). Given that our San A derivatives share no structural similarities to current drugs on the market we have the opportunity to use our novel approach to treat drug-resistant cancers.

HOST:

Jose Castillo

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