Light-Controlled Disruption of Cancer Cell Dormancy via Photoswitchable Stress Hormone Receptor Degraders

Arylazopyrazole-based GR photoPROTACs bearing Me2- and (OEt)2 substituents exhibited near-quantitative photoisomerization (95% Z-isomer; 89% – 92% E-isomer), no photobleaching, and thermal half-lives in the range of 3−12.2 days in DMSO. Among them, KH-5-306 and KH-5-309 induced potent, specific, and reversible GR degradation in their thermodynamically stable E-isomeric form at low nanomolar concentrations, with markedly reduced activity in the Z-isomeric state.

Transcriptomic profiling showed that E-KH-5-309 disrupts GR-driven dormancy-associated gene expression programs in a non-small cell lung cancer (NSCLC) model, while the Z-isomer remains functionally inert. Our findings establish a framework for the rational design of photoswitchable PROTACs beyond GR and demonstrate their potential to achieve spatiotemporal control of stress hormone receptor signaling, enabling mechanistic insights into GR function and the targeted disruption of cancer cell dormancy.