Small-Molecule-Targeting Hairpin Loop of hTERT Promoter G-Quadruplex Induces Cancer Cell Death

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Telomerase activity is elevated in many cancers, correlating with malignancy and poor prognosis.
• Directly targeting telomerase has yielded limited clinical success.
• Alternative strategies to inhibit telomerase are needed.

Purpose of the Study:

• To identify small molecules that selectively inhibit cancer cell growth by targeting the hTERT G-quadruplex.
• To investigate the mechanism of action of these novel compounds.
• To evaluate the efficacy and safety of a lead compound in preclinical models.

Main Methods:

• Synthesis and characterization of small molecules targeting the hTERT G-quadruplex.
• In vitro assays to assess cytotoxicity and mechanism of action (hTERT expression, mitochondrial function, oxidative stress, DNA damage, apoptosis).
• In vivo efficacy studies using tumor xenograft mouse models.

Main Results:

• Small molecules targeting the hTERT G-quadruplex selectively killed malignant cells.
• RG1603, a derivative of RG260, inhibited hTERT expression and induced mitochondrial defects (PGC1α and NRF2 inhibition).
• RG1603 demonstrated significant anticancer efficacy with tolerable toxicity in a xenograft model.

Conclusions:

• Targeting the hTERT G-quadruplex with small molecules offers a novel strategy for cancer therapy.
• RG1603 exhibits potent anticancer activity by inducing mitochondrial dysfunction and cell death.
• This approach provides a promising therapeutic avenue for cancers with elevated telomerase activity.