Recent advances in the development of telomerase inhibitors for the treatment of cancer

Perry, Philip J.; Jenkins, Terence C.

doi:10.1517/13543784.8.12.1981

Cited by 43 publications

(31 citation statements)

References 128 publications

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“…Recent reports emphasize that specific recognition of G-quadruplexes may be achieved (5)(6)(7)(8)(9)(10)(11)(12). Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalyzed by telomerase (6) and can therefore act as antitumor agents (13)(14)(15)(16)(17). We have designed a fluorescence resonance energy transfer (FRET) assay to identify such G-quadruplex ligands (G4 FRET; refs.…”

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confidence: 99%

Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands

Riou

Guittat

Mailliet

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

395

322

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Telomeres of human chromosomes contain a G-rich 3-overhang that adopts an intramolecular G-quadruplex structure in vitro which blocks the catalytic reaction of telomerase. Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalyzed by telomerase and can therefore act as antitumor agents. We have identified by Fluorescence Resonance Energy Transfer a new series of quinoline-based G-quadruplex ligands that also exhibit potent and specific anti-telomerase activity with IC 50 in the nanomolar concentration range. Long term treatment of tumor cells at subapoptotic dosage induces a delayed growth arrest that depends on the initial telomere length. This growth arrest is associated with telomere erosion and the appearance of the senescent cell phenotype (large size and expression of ␤-galactosidase activity). Our data show that a G-quadruplex interacting agent is able to impair telomerase function in a tumor cell thus providing a basis for the development of new anticancer agents.telomerase inhibitor ͉ tetraplex ͉ drug-DNA recognition

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mentioning

confidence: 99%

Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands

Riou

Guittat

Mailliet

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

395

322

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“…All of these unique conformations may play important functional roles in gene expression. Consequently, there is intense current interest in the design and synthesis of small molecules that selectively target specific DNA structures, to inhibit the biological function in which these particular structures participate (3)(4)(5)(6)(7)(8)(9)(10).…”

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confidence: 99%

Allosteric, chiral-selective drug binding to DNA

Trent

Fokt

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

155

150

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DNA is polymorphic and exists in a variety of distinct conformations (1, 2). Duplex DNA can adopt a variety of sequence-dependent secondary structures that range from the canonical right-handed B form through the left-handed Z conformation. Multistranded triplex and tetraplex structures are now known to exist. All of these unique conformations may play important functional roles in gene expression. Consequently, there is intense current interest in the design and synthesis of small molecules that selectively target specific DNA structures, to inhibit the biological function in which these particular structures participate (3-10).Enantiomers of chiral metal complexes have attracted considerable attention as potential structural probes of DNA conformation. Norden and Tjerneld (11) first reported the preference of the ⌬ enantiomer of Tris(dipyridyl)Fe(II) for right-handed B-form DNA. The Barton laboratory subsequently developed an elaborate series of chiral metal complexes, some of which were reported to recognize specific DNA conformational features (for reviews, see refs. 12-14). A comprehensive review of the interaction of chiral metal complexes with DNA (15) indicated, however, that the structural selectivity of these agents is ambiguous in many cases.We report here a dramatic and unambiguous example of structural selectivity in DNA binding for the naturally occurring anticancer agent (ϩ)-daunorubicin and its novel (Ϫ)-enantiomer, WP900 (Fig. 1). The synthesis of WP900 proved to be demanding and required some 37 steps. We find that the daunorubicin͞WP900 enantiomeric pair can discriminate between right-and left-handed DNA, and that each compound can act as an allosteric effector to convert DNA to a conformation that binds each ligand with higher affinity. The structural selectivities of daunorubicin and WP900 appear to be far greater than those reported to date for any chiral metal compound. To the best of our knowledge, there have been no other reports of a detailed investigation of DNA binding for an enantiomeric pair that does not involve a chiral metal complex. Materials and MethodsMaterials. Daunorubicin was obtained from Sigma and was used without further purification. The concentrations of daunorubicin solutions were determined by optical absorption at 480 nm by using 480 ϭ 11,500 M Ϫ1 ⅐cm Ϫ1

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“…Second, they penetrate into the cell nucleus with greater efficacy, probably by active transport mechanisms (24), which should potentially allow lower dosage and ultimately make treatment less toxic. Finally, in addition to the advantages above DNA tetraplex forming oligonucleotides have the capacity to inhibit telomerase (25), which is essential for transformation and immortalization of most neoplastic cell types (26). In the context of the recent important link that the c-MYC protein regulates expression of the telomerase catalytic subunit (27), we conjecture that the DNA tetraplex forming oligonucleotides we use to suppress c-myc, directly or indirectly may also influence telomerase activity.…”

Section: Discussionmentioning

confidence: 94%