PHOTACs enable optical control of protein degradation. Academic Article uri icon

Overview

abstract

  • PROTACs (PROteolysis TArgeting Chimeras) are bifunctional molecules that target proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins. We now introduce photoswitchable PROTACs that can be activated with the spatiotemporal precision that light provides. These trifunctional molecules, which we named PHOTACs (PHOtochemically TArgeting Chimeras), consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated with different wavelengths of light. Our modular approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.

publication date

  • February 21, 2020

Research

keywords

  • Optical Phenomena
  • Proteolysis

Identity

PubMed Central ID

  • PMC7034999

Scopus Document Identifier

  • 85079849383

Digital Object Identifier (DOI)

  • 10.1126/sciadv.aay5064

PubMed ID

  • 32128406

Additional Document Info

volume

  • 6

issue

  • 8