title: Oligonucleotide N3' --> P5' thio-phosphoramidate telomerase template antagonists as potential anticancer agents.
abstract: Human telomerase is a reverse transcriptase that is expressed in essentially all cancer cells, but not in the vast majority of normal somatic cells. Therefore, the specific inhibition of telomerase activity in tumors might have significant beneficial therapeutic effects. We have designed and evaluated oligonucleotide N3' --> P5' thio-phosphoramidates as telomerase template antagonists. In biochemical cell-free assays 11-13-mer thio-phosphoramidate oligonucleotides demonstrated sequence specific and dose dependent inhibition of telomerase with pico-molar IC50 values. Optimization of the oligonucleotide sequence and length resulted in the identification of a 13-mer-oligonucleotide thio-phosphoramidate GRN163 as a drug development candidate. In cell cultures GRN163 was able to inhibit telomerase activity in the absence of cationic lipid with approximately 1 microM IC50 values. Telomerase inhibition by GRN163 produced gradual telomere shortening, followed by cellular senescence and/or apoptosis of cancer derived cell lines.
authors.affiliation: Geron Corporation, Menlo Park, California 94025, USA. sgryaznov@geron.com
authors.forename: Sergei
authors.initials: S
authors.lastname: Gryaznov
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oshima
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Krisztina
authors.initials: K
authors.lastname: Pongracz
authors.forename: Ronald
authors.initials: R
authors.lastname: Pruzan
authors.forename: Ellen
authors.initials: E
authors.lastname: Wunder
authors.forename: Mieczyslaw
authors.initials: M
authors.lastname: Piatyszek
authors.forename: Shihong
authors.initials: S
authors.lastname: Li
authors.forename: Allison
authors.initials: A
authors.lastname: Chin
authors.forename: Calvin
authors.initials: C
authors.lastname: Harley
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamashita
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects*; D015195:Drug Design; D006801:Humans; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010710:Phosphates / Q000737:chemistry / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D013698:Templates, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009841:Oligonucleotides; D010710:Phosphates; D019098:Telomerase; C035638:thiophosphoric acid