- Approach to Discovery
- Our Portfolio
- Phortress - CYP-activated , DNA-interactive agent (breast, ovarian, renal, lung)
- PMX 500 - Telomere targeting agents (broad spectrum activity)
- PMX 700 - repair resistant DNA-interactive agents (broad spectrum activity)
- PMX 900 - Base Excision Repair inhibitors, undisclosed target (broad spectrum activity)
- About Cancer
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PMX 500 Programm - Telomere Targeting Agents
The PMX 500 telomere targeting agent programme is a world-leading programme focused on the design of compounds that selectively stabilise quadruplex DNA and in so doing block the ability of telomerase to act on linear duplex DNA in order to elongate telomeres and sustain cell survival. Our compounds have been shown to promote the disruption of telomere-"capping" proteins that protect telomeres from degradation by nuclease and end-to-end fusion. The current lead compound class has demonstrated potent single-agent anti-tumour activity in xenograft studies against a range of solid tumours, including breast, colon, lung, prostate and melanoma, and acts synergistically in combination with irinotecan in vitro and in vivo, where enhanced efficacy has translated into a significant increase in median survival time. Our aim is to identify a compound with good tolerability for progression as a clinical candidate. Our expectation is that compounds from this class will have utility in the treatment of a broad range of tumour types.
Telomere Function
Telomeres are repetitive, guanine rich TTAGGG DNA sequences ("telomeric DNA") at the ends of chromosomes and their associated protective "capping" proteins. The role of telomeres and the related enzyme telomerase, and their potential value as targets for anti-cancer therapy, was first elucidated by Professor Elizabeth Blackburn and colleagues in the 1980s. The scientific importance of their groundbreaking work was recognised by the award of the 2009 Nobel Prize for Physiology or Medicine.
In human cells, the telomeric DNA possesses a 100-200 nucleotide single stranded overhang region at the 3'-end. This prevents complete replication during normal cell division resulting in progressive shortening of the telomeres. 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, which adds TTAGGG repeats to the end of chromosomes, preventing telomere shortening and allowing 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 the potential for efficacy in many tumour types
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