An Orally Available Telomeric G-Quadruplex Ligand Induces Telomere Crisis and Dual DNA/RNA-Sensing Innate Immunity...

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Telomere crisis is a key barrier to cancer cell proliferation.
• The cGAS-STING and TERRA-ZBP1 pathways are implicated in sensing DNA and RNA, respectively, offering therapeutic targets.
• Targeting telomeres presents a promising anticancer strategy.

Purpose of the Study:

• To discover and characterize novel compounds that induce telomere crisis for cancer therapy.
• To investigate the mechanism of action of CA11, a G-quadruplex ligand.
• To evaluate the efficacy and safety of CA11 in preclinical cancer models.

Main Methods:

• G-quadruplex-focused screening platform to identify CA11.
• Pharmacological stabilization of telomeric G4s using CA11.
• Assessment of telomere crisis-like phenotype and innate immune pathway activation (DNA/RNA sensing).
• Evaluation of antiproliferative effects in cancer cell lines and tumor growth suppression in vivo.
• Systemic tolerability assessment.

Main Results:

• CA11, an orally bioavailable quinazoline derivative, was identified.
• CA11 stabilizes telomeric G4s, inducing a telomere crisis-like phenotype.
• Coordinated activation of dual DNA/RNA-sensing innate immune pathways was observed.
• CA11 demonstrated broad antiproliferative effects and suppressed tumor growth in vivo.
• CA11 was well tolerated systemically.

Conclusions:

• CA11 is the first-in-class, orally activated telomeric G4 ligand.
• CA11 pharmacologically induces telomere crisis, activating innate immunity and autophagy.
• CA11 exhibits potent anticancer activity and is a promising candidate for cancer therapy.