Oligonucleotide N3' --> P5' thio-phosphoramidate telomerase template antagonists as potential anticancer agents.
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.
Gryaznov
Sergei
S
Geron Corporation, Menlo Park, California 94025, USA. sgryaznov@geron.com
Asai
Akira
A
Oshima
Yuko
Y
Yamamoto
Yoshihiro
Y
Pongracz
Krisztina
K
Pruzan
Ronald
R
Wunder
Ellen
E
Piatyszek
Mieczyslaw
M
Li
Shihong
S
Chin
Allison
A
Harley
Calvin
C
Akinaga
Shiro
S
Yamashita
Yoshinori
Y
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
D000970:Antineoplastic Agents; D009841:Oligonucleotides; D010710:Phosphates; D019098:Telomerase; C035638:thiophosphoric acid