Spatiotemporally controlled degradation of CDK6 via light-triggered ROS generation: uncovering the proximity effect-mediated dual target depletion.

Abstract

Cyclin-dependent kinase 6 (CDK6) is a key therapeutic target in breast cancer, and its abnormal activation, together with Cyclin D3, promotes uncontrolled cell proliferation. Traditional CDK4/6 inhibitors only inhibit kinase activity without degrading the target protein, which readily causes drug resistance. In this study, we designed and synthesized a series of photo-controlled CDK6 degraders (LL1-LL7) using palbociclib as the core pharmacophore and linking photosensitizers to generate reactive oxygen species (ROS) under light. Among them, LL5 showed the best CDK6 degradation and antiproliferative activity. LL5 produces ROS via a Type II mechanism under 450 ± 25 nm LED light and elevates intracellular ROS in T47D cells. Western blot revealed that LL5 barely affected CDK6 and Cyclin D3 in the dark but markedly degraded both proteins after 15 min of irradiation, owing to ROS-mediated structural damage and the proximity effect between the two proteins. Functional assays showed that light irradiation significantly enhanced the antiproliferative activity of LL5. It displayed good selectivity between cancer and normal breast epithelial cells and induced G0/G1 arrest and apoptosis in T47D cells under light. In conclusion, LL5 acts as a photo-controlled degrader that co-degrades CDK6 and Cyclin D3 through light-triggered ROS and proximity effects, offering a promising new strategy for breast cancer treatment.