Drug Discovery Opinion

Telomeres are repetitive sequences at the 3’-end of DNA which protect the end of the chromosome from destruction during cell division. During the process, the telomeres are themselves destroyed and this mechanism normally limits cells to a fixed number of divisions. Embryonic stem cells express an enzyme, telomerase, which replaces the telomeres and allows the cells to divide repeatedly. Telomerase remains active in some rapidly dividing adult cells, but is switched off almost completely in most other cells to prevent excessive proliferation. Cancer cells often regain telomerase activity and are able to replicate indefinitely. Telomerase activity has been observed in approximately 90% of human tumours and inhibition of this enzyme is seen as a potential treatment for many cancers.

The telomerase is a reverse transcriptase that carries its own RNA primer sequence and has some similarities to the retroviral reverse transcriptases, viral RNA polymerases and B-family DNA polymerases. The first telomerase inhibitor to enter clinical trials for the treatment of cancer is GRN163L, a lipid-conjugated thiophosphoramidate. GRN163L is resistant to nuclease digestion in blood and tissues and has very high affinity and specificity for telomerase.

Small molecule inhibitors such as BIBR1532, which inhibits telomerase activity in vitro with an IC₅₀ in the low nanomolar range, have also been identified. The nucleoside analogue AZT, which is used to treat HIV by inhibiting the viral reverse transcriptase, weakly inhibits telomerase activity.
An advance online publication in the journal Nature describes a high resolution structure of the Tribolium castaneum catalytic subunit of telomerase, TERT (Telomerase Reverse Transcriptase).

It is hoped that the new structure will help in the design of small molecule telomerase inhibitors. As well as de novo design, the similarity between TERT and HIV reverse transcriptase suggests that it may be possible to modify reverse transcriptase inhibitors to inhibit telomerase. Such compounds could potentially be used to treat a wide range of cancers.

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