Recent Patents on Anti-Telomerase Cancer Therapy

Agrawal, Anita; Dang, Shweta; Gabrani, Reema

doi:10.2174/157489212798357958

Cited by 51 publications

(35 citation statements)

References 75 publications

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“…Several therapeutic strategies for overcoming activated telomerase have been explored, 2 including targeting the telomerase holoenzyme or the human telomerase reverse transcriptase (hTERT) subunit, targeting telomeric Gquadruplexes, inhibiting telomerase RNA, and using immune therapy directed at hTERT as a tumor antigen. Imetelstat, an antisense 13-mer oligonucleotide targeted to hTERT, has shown preclinical promise with anticancer activity in breast, brain, pancreas, and liver cancer models.…”

Section: Introductionmentioning

confidence: 99%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wildtype (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing.We show that promoter mutations exert a detrimental effect on the folding of one of these Gquadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression effects cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and inducing senescence by decreasing telomerase activity and telomere length.We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress hTERT.3

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Section: Introductionmentioning

confidence: 99%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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“…Significantly increased telomerase expression and activity has been observed in nearly 90 % of cancer cells, suggesting its potential as an anticancer drug target [19,20]. Currently, therapeutic approaches to inhibit telomerase activity have focused on small molecular inhibitors, gene therapy, and immune therapy [21][22][23][24][25]. Several antitumor drugs targeting telomeres and telomerase such as GRN163L have been developed and are currently in clinical trials (phase I/II) [26][27][28][29][30][31][32][33]; however, suppression of tumor growth by telomerase inhibition did not occur immediately.…”

Section: Introductionmentioning

confidence: 99%

A combination of the telomerase inhibitor, BIBR1532, and paclitaxel synergistically inhibit cell proliferation in breast cancer cell lines

et al. 2015

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Breast cancer is one of the most significant causes of female cancer death worldwide. Paclitaxel, an extensively used breast cancer chemotherapeutic has limited success due to drug resistance. 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532), a small molecule pharmacological inhibitor of telomerase activity, can inhibit human cancer cell proliferation as well. Thus, to enhance breast cancer treatment efficacy, we studied the combination of BIBR1532 and paclitaxel in breast cancer cell lines. Cell viability assays revealed that BIBR1532 or paclitaxel alone inhibited proliferation in a dose-dependent manner, and combining the drugs synergistically induced growth inhibition in all breast cell lines tested independent of their p53, ER, and HER2 status. The drug combination also synergistically inhibited colony formation of MCF-7 cells in a dose-dependent manner. Annexin V-PI staining and Western blot assays on PARP cleavage and caspase-8 and caspase-3 revealed that BIBR1532 in combination with paclitaxel was more potent than either agent alone in promoting MCF-7 cell apoptosis. Cell cycle analysis indicated that BIBR1532 induced a G1 phase arrest and paclitaxel arrested cells at the G2/M phase. The drug combination dramatically blocked S cells from entering the G2/M phase. Our results suggest the potential of telomerase inhibition as an effective breast cancer treatment and that used in conjunction with paclitaxel; it may potentiate tumor cytotoxicity.

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“…Studying anti-telomerase potential of various deoxyguanosine nucleotide analogs, Tendian et al [40] observed that 2', 3'-dideoxyguanosine 5'-triphosphate, 6-thio-2'-deoxyguanosine 5'-triphosphate (T-dGTP), carbovir 5' triphosphate (CBV-TP), and D-carbocyclic-2'-deoxyguanosine 5'-triphosphate (D-CdG-TP) were able to inhibit telomerase activity by 50% with half maximal inhibitory concentrations (IC50) of 3±2µM, 8±2µM, 6±1.5µM and 11±2µM, respectively. In addition, compounds such as 7-deaza-2'-deoxyguanosine-5'-triphosphate (7-deaza-dGTP) and 7-deaza-2'-deoxyadenosine-5'-triphosphate (7-deazadATP) potentially inhibited telomerase activity by competing with natural substrates dGTP and dATP, respectively and hence getting incorporated into telomeric DNA by telomerase [40].…”

Section: Telomerase Inhibitorsmentioning

confidence: 99%

“…In addition, compounds such as 7-deaza-2'-deoxyguanosine-5'-triphosphate (7-deaza-dGTP) and 7-deaza-2'-deoxyadenosine-5'-triphosphate (7-deazadATP) potentially inhibited telomerase activity by competing with natural substrates dGTP and dATP, respectively and hence getting incorporated into telomeric DNA by telomerase [40]. However, they act as poor substrates for telomerase and lead to the dissociation and decreased processivity of telomerase.…”

Section: Telomerase Inhibitorsmentioning

confidence: 99%

“…However, they act as poor substrates for telomerase and lead to the dissociation and decreased processivity of telomerase. All these studies shed light on the significance of reverse transcriptase inhibitors to be used as anti-telomerase agents but further work has to be done in this direction to find more novel potential reverse transcriptase inhibitors which can be used as anti-cancer agents [40].…”

Section: Telomerase Inhibitorsmentioning

confidence: 99%

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Molecular Modeling and Evaluation of Novel Dibenzopyrrole Derivatives as Telomerase Inhibitors and Potential Drug for Cancer Therapy

Kalathiya

Padariya

Bagiński

2014

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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During previous years, many studies on synthesis, as well as on anti-tumor, anti-inflammatory and anti-bacterial activities of the pyrazole derivatives have been described. Certain pyrazole derivatives exhibit important pharmacological activities and have proved to be useful template in drug research. Considering importance of pyrazole template, in current work the series of novel inhibitors were designed by replacing central ring of acridine with pyrazole ring. These heterocyclic compounds were proposed as a new potential base for telomerase inhibitors. Obtained dibenzopyrrole structure was used as a novel scaffold structure and extension of inhibitors was done by different functional groups. Docking of newly designed compounds in the telomerase active site (telomerase catalytic subunit TERT) was carried out. All dibenzopyrrole derivatives were evaluated by three docking programs: CDOCKER, Ligandfit docking (Scoring Functions) and AutoDock. Compound C_9g, C_9k and C_9l performed best in comparison to all designed inhibitors during the docking in all methods and in interaction analysis. Introduction of pyrazole and extension of dibenzopyrrole in compounds confirm that such compound may act as potential telomerase inhibitors.

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Recent Patents on Anti-Telomerase Cancer Therapy

Cited by 51 publications

References 75 publications

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

A combination of the telomerase inhibitor, BIBR1532, and paclitaxel synergistically inhibit cell proliferation in breast cancer cell lines

Molecular Modeling and Evaluation of Novel Dibenzopyrrole Derivatives as Telomerase Inhibitors and Potential Drug for Cancer Therapy

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