Ru(II) photocages enable precise control over enzyme activity with red light

Cytochrome P450 enzymes (CYPs) are essential in drug metabolism and signaling. CYP1B1 is overexpressed in multiple tumors and linked to chemotherapy resistance, but selective inhibition is challenging due to off-target effects on hepatic CYPs. The authors developed light-triggered, Ru(II)-photocaged CYP1B1 inhibitors that release active inhibitors upon red light (660 nm) irradiation, achieving greater than 6000-fold potency improvement upon activation and selectivity indices of 4,000–100,000 over other CYPs. Key design elements include coordinating CYP1B1 inhibitors that bind at picomolar concentrations in live cells via iron anchoring, and biocompatible Ru(II) scaffolds that cage inhibitors for photorelease. These Ru(II) photocages may enable similar selectivity and control for other coordinating CYP inhibitors.

Dmytro Havrylyuk, Austin C. Hachey, Alexander Fenton, David K. Heidary, Edith C. Glazer