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PHOTACs Enable Optical Control of Protein Degradation

revised on 31.05.2019, 19:43 and posted on 31.05.2019, 20:19 by Martin Reynders, Bryan Matsuura, Marleen Bérouti, Daniele Simoneschi, Antonio Marzio, Michele Pagano, Dirk Trauner

PROTACs (proteolysis targeting chimeras) are bifunctional molecules that tag 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 and are on the verge of being clinically used. We now introduce photoswitchable PROTACs that can be activated with the temporal and spatial precision that light provides. These trifunctional molecules, which we named PHOTACs, 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 to varying degrees with different wavelengths of light. Our modular and generalizable 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.


NIH OD016343

NIH R01-CA76584



Email Address of Submitting Author


New York University



ORCID For Submitting Author


Declaration of Conflict of Interest

M.R., B.M., M.B., D.T. are inventors on a patent application on PHOTACs. M.P. is a member of the scientific advisory boards of CullGen Inc. and Kymera Therapeutics and a consultant for BeyondSpring Pharmaceutical.

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