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Biochemistry and Biophysics |
Kyowa Hakko Kogyo, Ltd., Pharmaceutical Research Institute, Shizuoka 411-8731, Japan [A. A., Y. O., Y. Yamam., T-a. U., H. K., S. A., Y. Yamas.], and Geron Corporation, Menlo Park, California 94025 [K. P., R. P., E. W., M. P., S. L., A. C. C., C. B. H., S. G.]
Telomerase, the enzyme responsible for proliferative immortality, is expressed in essentially all cancer cells, but not in most normal human cells. Thus, specific telomerase inhibition is potentially a universal anticancer therapy with few side effects. We designed N3'
P5' thio-phosphoramidate (NPS) oligonucleotides as telomerase template antagonists and found that their ability to form stable duplexes with the telomerase RNA subunit was the key factor for antitelomerase activity. In biochemical assays 11–13-mer NPS oligonucleotides demonstrated sequence- and dose-dependent inhibition of telomerase with IC50 values <1 nM. Optimization of the sequence, length, and bioavailability resulted in the selection of a 13-mer NPS oligonucleotide, GRN163, as a drug development candidate. GRN163 inhibited telomerase in a cell-free assay at 45 ± 7 pM, and in various tumor cell lines at 
1 nM and approximately 0.3–1.0 µM in the presence and absence of carriers, respectively. GRN163 was competitive with telomeric primer binding, primarily because of hybridization to human telomerase RNA (hTR) component. Tumor cells treated with GRN163 in culture underwent telomere shortening, followed by cellular senescence or apoptosis after a period of time that generally correlated with initial telomere length. In a flank DU145 (prostate cancer) xenograft model, parenterally administered GRN163 caused suppression of tumor growth in the absence of gross toxicity. These data demonstrate that GRN163 has significant potential for additional development as an anticancer agent.
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