Activable Targeted Protein Degradation Platform Based on Light-triggered Singlet Oxygen

作者：Zhang, Silong^*; Li, Yuanyuan; Li, Tao; Zhang, Yu; Li, Haimei; Cheng, Zhengzai; Peng, Na; Liu, Yi; Xu, Juan^*; He, Huan^*

来源：Journal of Medicinal Chemistry, 2022, 65(4): 3632-3643.

DOI：10.1021/acs.jmedchem.1c02037

• SPATIOTEMPORAL CONTROL
• SELECTIVE DEGRADATION
• PHOTODYNAMIC THERAPY

Targeted protein degradation technologies (e.g., PROTACs) that can selectively degrade intracellular protein are an emerging class of promising therapeutic modalities. Herein, we describe the conjugation of photosensitizers and protein ligands (PS-Degrons), as an activable targeted protein degradation platform. PS-Degrons are capable of degrading protein of interest via light-triggered O-1(2), which is orthogonal and complementary to existing technologies. This generalizable platform allows controllable knockdown of the target protein with high spatiotemporal precision. Our lead compound PSDalpha induces a complete degradation of human estrogen receptor alpha (ER alpha) under visible light. The high degrading ERa efficacy of PSDalpha enables an excellent anti-proliferation performance on MCF-7 cells. Our results establish a modular strategy for the controllable degradation of target proteins, which can hopefully overcome the systemic toxicity in clinical treatment of PROTACs. We anticipate that PS-Degrons would open a new chapter for biochemical research and for the therapeutics.