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Merck

PHOTACs enable optical control of protein degradation.

Science advances (2020-03-05)
Martin Reynders, Bryan S Matsuura, Marleen Bérouti, Daniele Simoneschi, Antonio Marzio, Michele Pagano, Dirk Trauner
RESUMEN

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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Sigma-Aldrich
Anti-α-tubulina monoclonal antibody produced in mouse, clone B-5-1-2, purified from hybridoma cell culture
Sigma-Aldrich
Anti-γ-Tubulin antibody, Mouse monoclonal, clone GTU-88, ascites fluid
Sigma-Aldrich
Lenalidomide-Photoswitch2-NH2 hydrochloride, ≥95%
Sigma-Aldrich
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Sigma-Aldrich
Thalidomide-Photoswitch3-NH2 hydrochloride, ≥95%