The sansalvamide A (San A) scaffold is a promising structure for the development of novel cancer therapeutics. We have used the San A scaffold to produce 7 compounds that are cytotoxic to pancreatic and colon cancer cell lines at nanomolar concentrations. The San A derivatives are of particular interest because they do not share structural homology with other classes of marketed cancer therapeutics, they appear to inhibit an established target (Hsp90) at a novel site, and they are significantly more potent than the drugs currently available for the treatment of colon and pancreatic cancer. Known Hsp90 inhibitors interact with the N-terminal domain whereas our compounds are unique in that they target the C-terminal domain and block the binding of inositol hexakisphosphate kinase 2 (IP6K2). It is the overall goal of this project to develop a novel chemotherapeutic agent based on the San A scaffold. It is our hypothesis that analogs of San A with even greater potency and selectively can be synthesized by modifying key structural features identified in our preliminary studies.
The specific aims are to: a) Identify the binding site at the C-terminus of Hsp90 and design a potent second-generation lead candidate compound, b) Identify the key cellular targets and their role in San A's cytotoxic effect, and c) Identify the key cellular targets and their role in San A's cytotoxic effect.

Public Health Relevance

Cancers have continued to evolve new mechanisms of action that make them resistant to most known chemotherapeutic agents. Consequently, there remains a serious and immediate need for the development of antitumor agents that target drug-resistant cancers. The goal of this project involves using conformational based design to synthesize potent new anticancer agents that act via binding to the C-terminus of Hsp90 thus inhibiting the binding of inositol hexakisphosphate kinase 2 (IP6K2). Current lead compounds show promise for binding to this novel site and show potent cytotoxicity (nanomolar) as well as differential selectivity for cancer over normal cells. Through the proposed structural studies of our lead compounds with their biological targets combined with synthesis and in vivo studies, we anticipate generating a new class of therapeutic agents that may be useful in treating cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA137873-04
Application #
8265010
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Misra, Raj N
Project Start
2009-05-24
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$296,393
Indirect Cost
$21,955
Name
University of New South Wales
Department
Type
DUNS #
751020900
City
Sydney
State
Country
Australia
Zip Code
2052
McConnell, Jeanette R; Alexander, Leslie A; McAlpine, Shelli R (2014) A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response. Bioorg Med Chem Lett 24:661-6
Kim, Seong Jong; Ramsey, Deborah M; Boyer, Cyrille et al. (2013) Effectively delivering a unique hsp90 inhibitor using star polymers. ACS Med Chem Lett 4:
Ramsey, Deborah M; McAlpine, Shelli R (2013) Halting metastasis through CXCR4 inhibition. Bioorg Med Chem Lett 23:20-5
Kim, Seong Jong; McAlpine, Shelli R (2013) Solid phase versus solution phase synthesis of heterocyclic macrocycles. Molecules 18:1111-21
McConnell, Jeanette R; Rananaware, Dimple P; Ramsey, Deborah M et al. (2013) A potential rhodium cancer therapy: studies of a cytotoxic organorhodium(I) complex that binds DNA. Bioorg Med Chem Lett 23:2527-31
McConnell, Jeanette R; McAlpine, Shelli R (2013) Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorg Med Chem Lett 23:1923-8
Kim, Seong Jong; Lin, Chun Chieh; Pan, Chung-Mao et al. (2013) A structure-activity relationship study on multi-heterocyclic molecules: two linked thiazoles are required for cytotoxic activity. Medchemcomm 4:406-410
Ramsey, Deborah M; Amirul Islam, Md; Turnbull, Lynne et al. (2013) Psammaplysin F: a unique inhibitor of bacterial chromosomal partitioning. Bioorg Med Chem Lett 23:4862-6
Singh, Erinprit K; Ramsey, Deborah M; McAlpine, Shelli R (2012) Total synthesis of trans,trans-Sanguinamide B and conformational isomers. Org Lett 14:1198-201
Davis, Melinda R; Singh, Erinprit K; Wahyudi, Hendra et al. (2012) Synthesis of sansalvamide A peptidomimetics: triazole, oxazole, thiazole, and pseudoproline containing compounds. Tetrahedron 68:1029-1051

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