The sansalvamide A (San A) scaffold is a promising structure for the development of novel cancertherapeutics. We have used the San A scaffold to produce 7 compounds that are cytotoxic to pancreatic andcolon cancer cell lines at nanomolar concentrations. The San A derivatives are of particular interest becausethey do not share structural homology with other classes of marketed cancer therapeutics, they appear toinhibit an established target (Hsp90) at a novel site, and they are significantly more potent than the drugscurrently available for the treatment of colon and pancreatic cancer. Known Hsp90 inhibitors interact with theN-terminal domain whereas our compounds are unique in that they target the C-terminal domain and block thebinding of inositol hexakisphosphate kinase 2 (IP6K2). It is the overall goal of this project to develop a novelchemotherapeutic agent based on the San A scaffold. It is our hypothesis that analogs of San A with evengreater potency and selectively can be synthesized by modifying key structural features identified in ourpreliminary studies.
The specific aims are to: a) Conduct structure-activity studies of San A derivatives andselect a lead candidate compound, b) Identify the key cellular targets and determine the mechanism by whichSan A analogs kill tumor cells, and c) Determine the efficacy and toxicity of a lead San A derivative in colonand pancreatic xenograft models.
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