Telomerase as a Cancer Target. Development of New Molecules

Abstract

Telomeres are the terminal part of the chromosome containing a long repetitive and noncodifying sequence that has as function protecting the chromosomes. In normal cells, telomeres lost part of such repetitive sequence in each mitosis, until telomeres reach a critical point, triggering at that time senescence and cell death. However, in most of tumor cells in each cell division a part of the telomere is lost, however the appearance of an enzyme called telomerase synthetize the segment that just has been lost, therefore conferring to tumor cells the immortality hallmark. Telomerase is significantly overexpressed in 80-95% of all malignant tumors, being present at low levels in few normal cells, mostly stem cells. Due to these characteristics, telomerase has become an attractive target for new and more effective anticancer agents. The capability of inhibiting telomerase in tumor cells should lead to telomere shortening, senescence and apoptosis. In this work, we analyze the different strategies for telomerase inhibition, either in development, preclinical or clinical stages taking into account their strong points and their caveats. We covered strategies such as nucleosides analogs, oligonucleotides, small molecule inhibitors, G-quadruplex stabilizers, immunotherapy, gene therapy, molecules that affect the telomere/ telomerase associated proteins, agents from microbial sources, among others, providing a balanced evaluation of the status of the inhibitors of this powerful target together with an analysis of the challenges ahead.

Fig. (1)

Schematic representation of telomerase and its associated proteins.

Fig. (2)

a) Structure of the most important inhibitory molecules belonging to each group. A) Nucleosides. B) Oligonucleotides. C) Small molecule inhibitors. D) Stabilizators of G quadruplex. E) Immunotherapeutic molecules. F) Gene therapy constructs. G) Molecules that target telomere and telomerase associated proteins. H) Inhibitors from microbial sources. I) Other inhibitors. b). Mechanism of action of the most important inhibitory molecules belonging to each group. A) AZT: Integrates into the telomeric DNA. B) PNA: This modified antisense oligonucleotide is complementary to sequences within or near the human telomeric template. C) BIBR1532: Competiting inhibitor of TERT and hTR. D) Telomestatin: stabilizes G cuadruplexes preventing hTR of recognizing the unfolded single stranded telomere overhang. E) Tertomide Generates telomerase specific T helper cells, activates antigen presenting cells and cytotoxic T cells, generating a good immune response. F) Imetelstat: A lipid=conjugated 13=mer oligonucleotide sequence that is complementary to hTR. G) Gedanamycin: targets the HSP90.P23 co.chaperone complex, required for maturation and activation of telomerase. H) Rubromycin: competitive interact with the hTERT and.or hTR subunits of telomerase enzyme. I) Oleic acid. The three-dimensional structure of the active site of telomerase (i.e., the binding site of the primer and dNTP substrate) might have a “pocket” that could “join” these compounds.