Future Developments

Given the relative safety of AZT and the fact that it has been used in some cancer patients, although its mechanism of action is not specific for telomerase, this aspect of its activity may warrant investigation in trials of other tumor types. BIBR1532 seems to be a good candidate for progression to clinical trials, given its oral bioavailability, the consistency of its cellular effects with those of a classic telomerase inhibitor and, indeed, the fact of its discovery in collaboration with large pharma. However, no significant new studies evaluating BIBR1532 have emerged recently. MST-312 may also be a candidate, given that several clinical trials of related polyphenols have been reported (Bettuzzi et al. 2006, Chow et al. 2001, Chow et al. 2003). However, although telomerase inhibition, telomere shortening, and cell growth inhibition have been demonstrated for both compounds, telomerase-negative normal control cells have not been used widely, and their activity has been demonstrated in relatively few cancer cells and very few xenograft models. The expected phenotypic lag will need to be considered when designing trials of these compounds. In contrast, telomere targeting agents appear to induce relatively rapid toxicity mediated through telomere uncapping. AS1410 is a derivative of BRACO19 under development by the UK-based Antisoma. Preclinical data relating to the activity of AS 1410 were reported at the 2005 AACR annual meeting (Kelland et al. 2005). In 2005, Antisoma announced an agreement with Heraeus to manufacture AS 1410 for a phase I trial, though recruitment appears not to have begun to date.

In general, given the diversity of potential targets and leads, it is disappointing that relatively few selective small molecule telomerase inhibitors have been developed and no clinical trials have been reported so far. There would appear to be a compelling argument that new small molecule inhibitors of telomerase need to be identified with some urgency. Since most lead attrition occurs during the clinical phases of development, in which the cost of failure is at its highest, it is essential to employ adequate preclinical lead validation studies based on well-designed models so that only the best candidates progress to clinical testing. Substantial attention must now be paid to ensuring that both existing and newly identified leads are more thoroughly tested in the context of robust models demonstrating all or most of the expected preclinical characteristics of an efficient telomerase inhibitor: target inhibition, lack of short-term toxicity in vitro, effects on telomeres and delayed onset senescence or apoptosis, specificity for cancer cells over normal cells, broad-spectrum targeting of cancer cell lines, and efficacy with minimal toxicity in vivo.

In order to identify more new leads with these desirable properties, we should now consider the best assay development strategies. Cell-based assays offer potential to identify partially validated hits with improved lead-like qualities at the earliest stages of discovery and offer a number of critical advantages over conventional biochemical screening assays. Firstly, purification of the target protein in a functional conformation is not required. Instead, the key requirement is a measurable marker of endogenous target inhibition such as a change in reporter activity, protein phosphorylation, or cell morphology. Cell-based assays thus provide a better format for early development of biomarkers in parallel with validation of the screening assay. Importantly, cell-based assays may also discriminate between different drug effects, such as antagonism versus agonism and identify hits that interact with different target conformations that may be present in a physiological setting. Furthermore, membrane-impermeable compounds are discarded at the earliest stage of screening, and nonspecific cytotoxicity is easily identified. There is increasing industry enthusiasm for cell-based assays and, in particular, for high content phenotypic assays in which multiple outputs may be measured in the same well and correlated with complex phenotypes such as apop-tosis, mitosis, or morphological change (Fox et al. 2006, Mitchison 2005). It is therefore likely that the use of cell-based screening could accelerate discovery of new small molecules targeting telomerase.

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