Telomere Targeting Chimera Enables Targeted Destruction of Telomeric Repeat-Binding Factor Proteins

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• Telomere shortening is a hallmark of normal aging cells.
• Cancer cells often reactivate telomerase to maintain telomere length, enabling uncontrolled proliferation.
• Telomeres and associated proteins are critical targets for anticancer therapies.

Purpose of the Study:

• To develop novel nucleotide-based proteolysis-targeting chimeras (PROTACs) for cancer therapy.
• To target and degrade telomeric repeat-binding factor 1/2 (TRF1/2), key regulators of telomere length.
• To evaluate the efficacy of these TeloTACs in cancer cell lines.

Main Methods:

• Design and synthesis of nucleotide-based PROTACs (TeloTACs).
• Assessment of TRF1/2 degradation in a VHL- and proteasome-dependent manner.
• Evaluation of telomere length dynamics and cancer cell proliferation inhibition.

Main Results:

• TeloTACs effectively degraded TRF1/2 in cancer cells.
• Degradation of TRF1/2 led to significant telomere shortening.
• Suppressed cancer cell proliferation was observed following TeloTAC treatment.
• Demonstrated selective killing of cancer cells overexpressing TRF1/2.

Conclusions:

• TeloTACs represent a novel nucleotide-based approach for targeting telomeres.
• This strategy effectively shortens telomeres and inhibits tumor cell growth.
• TeloTACs show potential as a broad-spectrum anticancer therapeutic agent.