Optochemical control of G1 cell cycle by regulating CDK4/6 degradation

Cancer progression is characterized by dysregulated G1/S phase transition mediated by CDK4/6-dependent Rb protein phosphorylation. Although CDK4/6 degraders show encouraging anti-tumor efficacy, it is highly desired to develop strategies to spatiotemporally control the release of active CDK4/6 degraders to further reduce adverse effects. In this study, we employ an optochemical strategy for CDK4/6 degradation by caging the CRBN ligand with a photoremovable protecting group. Light irradiation at 365 nm triggers photocleavage, thereby inducing CDK4/6 degradation via the ubiquitin-proteasome system. The resultant G1-phase arrest demonstrates spatial and temporal control over cell-cycle progression, reducing off-target effects of current therapies. This light-controlled system allows spatiotemporal CDK4/6 degradation and G1 cell-cycle arrest, providing a promising strategy to enhance specificity for cancer treatment and fundamental biological research.