Development of a photocaged CLIPTAC for spatiotemporal control of protein degradation

Proteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary therapeutic modality. However, their clinical translation is often hindered by high molecular weight, poor cellular permeability, and systemic off-target toxicity. To address these challenges, we report a photocaged click-assembled PROTAC (pcCLIPTAC) for the spatiotemporally controlled degradation of the BRD4 protein. Our system utilizes cycloalkene-based bioorthogonal handles and a light-sensitive photocaged tetrazine-thalidomide as PROTAC precursors. Intracellular PROTAC assembly is initiated by 365 nm UV irradiation, resulting in robust and time-dependent BRD4 degradation only upon light activation. Linker optimization revealed a divergent structure-activity relationship (SAR). While the bulky trans-cyclooctene (TCO) handle favored longer linkers, the compact and rigid cyclopropene (CP) handle achieved maximum potency with minimal linker length. Furthermore, proteomic profiling revealed distinct cycloalkene-dependent protein abundance profiles, with degradation of BRD4 following both TCO2- and CP1-based pcCLIPTAC treatment. These findings provide practical design principles for light-controllable click-assembled degraders and support pcCLIPTAC as a platform for spatiotemporally controlled protein degradation.