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

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

  • J Med Chem. 2022 Feb 24;65(4):3632-3643. doi: 10.1021/acs.jmedchem.1c02037.
Silong Zhang 1,  Yuanyuan Li 2,  Tao Li 1,  Yu Zhang 1,  Haimei Li 1,  Zhengzai Cheng 1,  Na Peng 1,  Yi Liu 1 3,  Juan Xu 4,  Huan He 1
Affiliations

Affiliations

  • 1 Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Institute of Advanced Materials and Nanotechnology, Wuhan University of Science and Technology, Wuhan 430081, P. R. China.
  • 2 School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, Wuhan 430023, P.R. China.
  • 3 College of Chemistry and Chemical Engineering & College of Environmental Science and Engineering, Tiangong University, Tianjin 300378, P. R. China.
  • 4 College of Chemistry and Chemical Engineering, Hubei Polytechnic University, Huangshi 435003, P. R. China.
PMID: 35164509 DOI: 10.1021/acs.jmedchem.1c02037
Abstract

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 1O2, 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 α (ERα) under visible LIGHT. The high degrading ERα 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.

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