Telomerase reverse transcriptase degradation via a rationally designed covalent proteolysis targeting chimera

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Telomerase reverse transcriptase (TERT) expression is crucial for cancer cell immortality and supports tumor growth through various functions.
• Current TERT inhibitors targeting catalytic activity may not address TERT's other cancer-promoting roles, potentially leading to therapy resistance.
• Developing novel strategies to degrade TERT is essential for effective cancer treatment.

Purpose of the Study:

• To design and synthesize a proteolysis targeting chimera (PROTAC) capable of inducing proteasomal degradation of TERT in cancer cells.
• To investigate the efficacy of the TERT-degrading PROTAC (NU-PRO-1) in cancer cells.
• To explore the potential of TERT-degrading PROTACs as a novel therapeutic strategy against cancer.

Main Methods:

• Structure-based design and modular synthesis were employed to create the PROTAC.
• Biochemical assays were utilized to evaluate TERT degradation and its effects.
• Cancer cells were treated with the PROTAC, and responses including DNA damage and repair were assessed post-irradiation.

Main Results:

• A novel PROTAC, NU-PRO-1, was successfully developed, linking a TERT inhibitor (NU-1) to an E3 ligase ligand.
• NU-PRO-1 induced VHL- and proteasome-dependent degradation of TERT in cancer cells.
• NU-PRO-1 delayed DNA repair post-irradiation and did not induce DNA damage independently, suggesting a role beyond catalytic inhibition.

Conclusions:

• TERT-degrading PROTACs, exemplified by NU-PRO-1, represent a promising new class of chemical probes for studying TERT's non-catalytic functions.
• This approach may offer a strategy to overcome resistance mechanisms associated with current telomerase inhibitors.
• Targeting TERT for degradation presents a potential therapeutic avenue for cancer treatment.