Dual-targeting of mitochondrial and c-Myc G-quadruplexes by a photoactive coumarin-benzothiazolium conjugate inhibits triple-negative breast cancer cell growth.

Targeting G-quadruplexes (G4s) presents a promising strategy for cancer therapy, but early-generation ligands often lack tumor selectivity. This study identified X-3, a novel photoactive coumarin-benzothiazolium conjugate, as a dual-targeted photosensitizer against triple-negative breast cancer (TNBC). X-3 localized to both mitochondria and the nucleus, where it specifically bound to mitochondrial and c-Myc G4s with high affinity. Upon light activation, X-3 demonstrated excellent phototoxicity and minimal dark toxicity. Mechanistically, X-3 disrupted mitochondrial bioenergetics by inhibiting mtDNA replication, elevating reactive oxygen species (ROS), and reducing ATP production. Concurrently, it suppressed c-Myc oncogenic expression, shifting the cellular balance toward c-Myc-mediated apoptosis. Validated through 2D and 3D tumor spheroid models, photoactivated X-3 significantly inhibited TNBC proliferation and induced robust cell death. These findings established X-3 as a prototypical, light-controlled anticancer agent integrating molecular targeting precision with photodynamic safety.