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. Epub 2022 Feb 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Estrogen Receptor alpha / drug effects
  • Estrogen Receptor alpha / metabolism
  • Female
  • Humans
  • Ligands
  • Light
  • MCF-7 Cells
  • Models, Molecular
  • Photosensitizing Agents / chemical synthesis
  • Photosensitizing Agents / pharmacology
  • Proteins / chemistry
  • Proteins / radiation effects*
  • Reactive Oxygen Species / chemistry*
  • Reactive Oxygen Species / radiation effects*
  • Ubiquitin-Protein Ligases

Substances

  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Ligands
  • Photosensitizing Agents
  • Proteins
  • Reactive Oxygen Species
  • Ubiquitin-Protein Ligases