Telomerase inhibitors: targeting the vulnerable end of cancer?

In the past decade, a great deal has been learnt about the maintenance of telomeres in mammalian cells by the specialized reverse transcriptase, telomerase, and its associated proteins. The catalytic component of telomerase, hTERT, appears to be selectively activated in the vast majority of tumors relative to most somatic cells suggesting that its inhibition may result in antitumor effects. Although beset with some unusual issues as a drug target, recent 'target validation' studies using hTERT dominant-negative and antisense approaches strongly support the view that potent and selective telomerase inhibitors will induce inhibitory effects on tumors, especially in those possessing relatively short telomeres. Inhibitory strategies have focused on three main areas: antisense molecules (oligonucleotides, RNA molecules, ribozymes and peptide nucleic acids) directed against the hTR RNA component of telomerase, small molecule reverse transcriptase inhibitors (e.g. azidothymidine), and, probably most advanced, small molecules capable of interacting with and stabilizing four-stranded (G-quadruplex) structures formed by telomeres. G-quadruplex interactive agents that inhibit telomerase at sub-micromolar concentrations in cell-free assays have been described. Lead optimization and preclinical whole-cell and animal antitumor and pharmacology studies are now progressing which should result in the first generation of telomerase inhibitors being evaluated in the clinic within the next few years.