2. Academic Validation
  3. PHOTACs enable optical control of protein degradation

PHOTACs enable optical control of protein degradation

  • Sci Adv. 2020 Feb 21;6(8):eaay5064. doi: 10.1126/sciadv.aay5064.
Martin Reynders 1 2,  Bryan S Matsuura 1,  Marleen Bérouti 1 2,  Daniele Simoneschi 3 4,  Antonio Marzio 3 4,  Michele Pagano 3 4 5,  Dirk Trauner 1 4 6
Affiliations

Affiliations

  • 1 Department of Chemistry, New York University, New York, NY 10003, USA.
  • 2 Department of Chemistry, Ludwig Maximilians University of Munich, 81377 Munich, Germany.
  • 3 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
  • 4 Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
  • 5 Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
  • 6 NYU Neuroscience Institute, New York University School of Medicine, New York, NY 10016, USA.
PMID: 32128406 DOI: 10.1126/sciadv.aay5064
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.

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