In human cells, the telomeric DNA is composed of tandem repeats of the guanine-rich sequence TTAGGG with a 100-200 nucleotide single stranded overhang region at the 3'-end. Telomeres act as buffer zones, protecting cells from the consequences of incomplete replication of the chromosome ends by DNA polymerase during normal cell division, in which the terminal 50-200 base pairs of DNA are lost. When telomeres attain a critically short length, normal cells stop growing and enter a state of senescence.

In contrast, tumour cells are able to maintain their telomere length and in most cases this can be attributed to activation of the enzyme, telomerase. This adds TTAGGG repeats to the end of chromosomes and in so doing prevents telomere shortening and allows continued cell proliferation. Whilst there is little constitutive expression of telomerase in most normal tissues the enzyme is active in 85 - 95% of all human tumours. As such, agents that have the ability to inhibit the effects of telomerase and/or target the telomeres themselves are expected to have utility across a broad range of tumours.

RHPS4 has dual function activity against telomeres by promoting:

• Telomere shortening
• Dissociation of protective telomere "capping" protein

In vivo activity has been demonstrated against a number of human-derived tumour xenografts in the mouse when administered as a single agent and in combination with standard chemotherapeutics. Efficacy in preclinical studies has been observed following intravenous and oral administration of simple aqueous-based formulations. We are therefore committed to the continued development of this candidate.

Pharminox has entered into an agreement with Cancer Research Technology, the technology transfer arm of Cancer Research UK, securing rights to a preclinical programme focused on telomere targeted agents (TTAs) for the treatment of cancer. Under the terms of the agreement, Pharminox has an exclusive option to license from CRT exclusive worldwide rights to this programme in the field of human disease.

Telomere shortening

RHPS4 has been shown to stabilize the four-stranded G-quadruplex structures formed by the guanine-rich region of telomeres thereby inhibiting telomere replication by blocking the elongation step catalysed by telomerase by a reverse transcriptase mechanism. This results in telomere shortening and ultimately apoptosis.

Dissociation of protective telomere "capping" protein

RHPS4 exerts a short term effect of inducing cellular apoptosis and senescence by a mechanism that involves dissociation of the telomeric "capping" protein, POT1 (Protection of telomeres 1). This has been shown to be independent of basal telomere length and telomere shortening. Uncapping of telomeres renders the chromosomes susceptible to nuclease degradation.

In Vivo Activity

In vivo activity of RHPS4 has been demonstrated in the mouse against a number of human-derived tumour xenografts, including breast, melanoma, colon, lung, prostate and uterus. Efficacy has been observed following administration as a single agent and in combination with standard chemotherapeutics.