Research progress of small-molecule drugs in targeting telomerase in human cancer and aging

 

Research Progress of Small-Molecule Drugs in Targeting Telomerase in Human Cancer and Aging

Introduction

Telomerase is a ribonucleoprotein enzyme that maintains telomere length, playing a key role in cellular immortality. While it is largely inactive in most somatic cells, telomerase is abnormally activated in ~85–90% of cancers. In aging, reduced telomerase activity contributes to telomere shortening, genomic instability, and cellular senescence. Hence, telomerase represents a dual therapeutic target: inhibition for cancer and activation for age-related disorders.

1. Telomerase Structure and Function

• Composed mainly of two core components: TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component).

• Adds TTAGGG repeats to telomeres, preventing shortening during DNA replication.

• Its activity is tightly regulated and essential for stem cell renewal and genomic stability.

2. Telomerase in Cancer

• Overexpressed TERT enables cancer cells to bypass senescence and apoptosis.

• Small-molecule telomerase inhibitors aim to block TERT or its complex assembly, leading to telomere shortening and cancer cell death.

Key Inhibitors in Cancer Research:

Drug Name	Mechanism	Status
Imetelstat (GRN163L)	Oligonucleotide targeting TERC	Clinical trials (myelofibrosis, solid tumors)
BIBR1532	Non-nucleosidic TERT inhibitor	Preclinical
MST-312	Derivative of epigallocatechin gallate (EGCG)	Preclinical
Costunolide analogs	Natural terpenoid derivatives	Investigational
Telomestatin	Stabilizes G-quadruplex DNA at telomeres, disrupting telomerase access	Preclinical

3. Telomerase in Aging

• Aging is associated with telomere attrition and reduced regenerative capacity.

• Activators of telomerase are being explored to delay aging-related degeneration, improve stem cell function, and enhance tissue repair.

Potential Activators:

Compound	Mechanism	Application
TA-65	Astragalus extract (cycloastragenol); promotes TERT expression	Dietary supplement, longevity studies
AGS-499	Synthetic telomerase activator	Neurodegenerative models
GRN510	TERT activation via RNA-based methods	Preclinical aging models

4. Challenges and Considerations

• Specificity: Avoiding off-target effects and ensuring selective action in cancer vs normal cells.

• Resistance: Cancer cells may develop compensatory pathways.

• Delivery: Effective targeting to tissues remains a hurdle.

• Risk in Aging Therapies: Long-term telomerase activation could increase cancer risk.

5. Recent Advances and Future Directions

• Combination therapies: Telomerase inhibitors with DNA-damaging agents or immune checkpoint inhibitors.

• Structure-based drug design: Advances in TERT crystal structure aid rational drug development.

• Nanoparticle delivery systems: For precise targeting of telomerase-modulating compounds.

• Gene editing and CRISPR: Emerging tools to directly modify telomerase-related genes.

  
  
  

1. Telomerase Biology: The Foundation

🔹 Components:

• TERT (Telomerase Reverse Transcriptase): The catalytic subunit with reverse transcriptase activity.

• TERC (Telomerase RNA Component): Serves as a template for adding telomeric repeats (TTAGGG).

• Accessory proteins: Dyskerin, NOP10, NHP2, GAR1—assist in RNP assembly and stability.

🔹 Function:

Telomerase maintains telomere length at chromosome ends, protecting DNA from damage. In most somatic cells, telomerase is silenced post-development, leading to gradual telomere shortening with each division. In stem cells, germ cells, and cancer, telomerase is active or reactivated to enable continued division.

2. Telomerase in Cancer: A Universal Hallmark

🔹 Reactivation:

In ~85–90% of cancers, TERT is upregulated through promoter mutations (C228T, C250T), gene amplification, or epigenetic derepression.

🔹 Implications:

• Enables replicative immortality.

• Protects from apoptosis and crisis.

• Enhances resistance to DNA-damaging therapy.

3. Small-Molecule Telomerase Inhibitors in Cancer Therapy

A. Imetelstat (GRN163L)

• Structure: 13-mer thio-phosphoramidate oligonucleotide with lipid moiety.

• Mechanism: Binds TERC RNA template → prevents elongation of telomeres.

• Clinical Trials:

  • Myelofibrosis (MF): Phase 2 shows reduction in mutant clones.

  • Acute Myeloid Leukemia (AML): Potential in leukemic stem cells.

B. BIBR1532

• Mechanism: Non-nucleosidic, allosteric inhibitor that directly binds TERT.

• Outcome: Telomere attrition, senescence, and apoptosis in tumor cells.

• Limitation: Requires long-term administration.

C. Telomestatin

• Mechanism: Binds and stabilizes G-quadruplex (G4) DNA at telomeres, preventing telomerase access.

• Source: Streptomyces species (natural product).

• Impact: Induces telomere dysfunction and DNA damage in glioblastoma, leukemia.

D. MST-312

• Structure: Synthetic analog of EGCG (from green tea).

• Mechanism: Inhibits TERT enzymatic activity.

• Effect: Telomere shortening and ROS-related DNA damage.

E. Other Experimental Compounds

• TMPyP4: G4 binder, disrupts telomere maintenance.

• Costunolide analogs: Natural sesquiterpene lactones inhibit TERT transcription.

• 6-thio-dG: Gets incorporated into telomeres, inducing dysfunction and apoptosis in telomerase-positive cells.

4. Telomerase Activators in Aging and Regeneration

A. Aging and Telomerase Decline

• Telomere shortening triggers cellular senescence, mitochondrial dysfunction, and age-related degeneration.

• Reactivation of telomerase may delay aging, improve stem cell function, and tissue repair.

B. TA-65 (Cycloastragenol)

• Source: Astragalus membranaceus (traditional Chinese herb).

• Mechanism: Activates TERT transcription through estrogen and MAPK pathways.

• Use: Marketed as a nutraceutical supplement; limited clinical data.

• Studies: Some show improved immune profiles and metabolic markers.

C. GRN510

• Mechanism: Increases TERT mRNA expression in vitro.

• Application: Preclinical success in lung fibrosis models.

D. AGS-499

• Synthetic compound developed for neurodegenerative conditions.

• Shown to improve memory and neuroplasticity in animal aging models via telomerase activation.

E. Gene Therapy and mRNA Delivery

• TERT mRNA delivery has shown lifespan extension in mice.

• AAV-mediated TERT gene therapy increased survival and delayed aging signs without increasing cancer in models.

5. Pathways Regulating Telomerase Expression

Pathway	Role in TERT Regulation
MYC	Directly activates TERT promoter
MAPK/ERK	Enhances TERT mRNA stability
NF-κB	Upregulates TERT in inflammation/cancer
Wnt/β-catenin	Activates TERT transcription
p53/p21/Rb	Suppresses telomerase under DNA damage
Epigenetic	TERT promoter methylation, histone acetylation

6. Current Clinical Landscape

Compound	Indication	Phase	Outcome
Imetelstat	MF, MDS, AML	Phase 2	Clinical benefit, telomerase inhibition validated
TA-65	Aging	Supplement	Mixed results, needs RCTs
6-thio-dG	Solid tumors	Preclinical	Promising tumor-specific cytotoxicity
Telomestatin	Glioma, leukemia	Preclinical	Strong anti-proliferative effects

7. Limitations and Considerations

• Inhibitors:

  • Delayed effect due to slow telomere shortening.

  • Off-target effects and resistance development.

  • Potential stem cell damage.

• Activators:

  • Cancer risk from indiscriminate telomerase reactivation.

  • Long-term safety still under investigation.

8.Future Directions

• Biomarker-guided therapy: TERT promoter mutation screening.

• Telomerase + Immunotherapy: Boosting antigenicity of cancer cells.

• Synthetic biology: Designer molecules to control telomerase at will.

• 3D telomere mapping: Personalized telomere-targeted treatments.

 Conclusion

Small-molecule drugs targeting telomerase represent a transformative approach in oncology and regenerative medicine. While inhibitors aim to combat uncontrolled proliferation in cancer, activators seek to rejuvenate tissues and combat aging. Continued research is crucial to balancing efficacy with safety in telomerase modulation.