Telomerase activity has been found in 85-95 percent of all primary tumors that have been assayed, but not in somatic cells with the exception of germ cells and proliferative cells of renewal tissues (which express low levels). The connection between telomerase and cancer has led to the hypothesis that telomerase activity is necessary for sustained proliferation of most cancer cells, and that telomerase inhibitors might be effective chemotherapeutic agents. The objective of this proposal is the development of telomerase inhibitors as tools to validate the connection between telomerase and cancer. Such inhibitors would be lead compounds for the design of anti-telomerase therapeutics and further the understanding of the interplay between telomerase and other cellular proteins.
Specific aims of this proposal include the discovery and optimization of new inhibitor chemistries in vitro, the use of inhibitors as structural and functional probes for telomerase, and the use of the inhibition of telomerase activity to help resolve whether telomerase activity is necessary for cell immortality.
|Li, Yingming; Malaeb, Bahaa S; Li, Zhong-Ze et al. (2010) Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer. Prostate 70:616-29|
|Shay, Jerry W; Wright, Woodring E (2002) Telomerase: a target for cancer therapeutics. Cancer Cell 2:257-65|
|Elayadi, A N; Demieville, A; Wancewicz, E V et al. (2001) Inhibition of telomerase by 2'-O-(2-methoxyethyl) RNA oligomers: effect of length, phosphorothioate substitution and time inside cells. Nucleic Acids Res 29:1683-9|
|Braasch, D A; Corey, D R (2001) Synthesis, analysis, purification, and intracellular delivery of peptide nucleic acids. Methods 23:97-107|
|Elayadi, A N; Corey, D R (2001) Application of PNA and LNA oligomers to chemotherapy. Curr Opin Investig Drugs 2:558-61|
|Corey, D R (2000) Telomerase: an unusual target for cytotoxic agents. Chem Res Toxicol 13:957-60|
|Mayfield, L D; Corey, D R (1999) Automated synthesis of peptide nucleic acids and peptide nucleic acid-peptide conjugates. Anal Biochem 268:401-4|
|Herbert, B; Pitts, A E; Baker, S I et al. (1999) Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci U S A 96:14276-81|
|Mayfield, L D; Corey, D R (1999) Enhancing solid phase synthesis by a noncovalent protection strategy-efficient coupling of rhodamine to resin-bound peptide nucleic acids. Bioorg Med Chem Lett 9:1419-22|
|Hamilton, S E; Simmons, C G; Kathiriya, I S et al. (1999) Cellular delivery of peptide nucleic acids and inhibition of human telomerase. Chem Biol 6:343-51|
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