scholarly journals Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications

2022 ◽  
Author(s):  
Nathaniel J. Henning ◽  
Andrew G. Manford ◽  
Jessica N. Spradlin ◽  
Scott M. Brittain ◽  
Erika Zhang ◽  
...  
Keyword(s):  
Protein Degradation

A Caged E3 Ligase Ligand for PROTAC-Mediated Protein Degradation with Light

2019 ◽  
Author(s):  
Cyrille Kounde ◽  
Maria M. Shchepinova ◽  
Edward Tate
Keyword(s):  
Protein Degradation ◽  
Irradiation Time ◽  
E3 Ligase ◽  
Von Hippel Lindau ◽  
Short Irradiation ◽  
Short Irradiation Time ◽  
Spatiotemporal Control

A caging group has been appended to a widely used Von Hippel Lindau (VHL) E3 ligase ligand for targeted protein degradation with PROTACs. Proteolysis is triggered only after a short irradiation time allowing spatiotemporal control of the protein’s fate.

PHOTACs Enable Optical Control of Protein Degradation

2019 ◽  
Author(s):  
Martin Reynders ◽  
Bryan Matsuura ◽  
Marleen Bérouti ◽  
Daniele Simoneschi ◽  
Antonio Marzio ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Optical Control ◽  
Cellular Proteins ◽  
Bifunctional Molecules ◽  
Protein Levels ◽  
Lead Compounds ◽  
Subsequent Degradation ◽  
Temporal And Spatial ◽  
Precision Therapeutics

<p><i>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.</i><b></b></p>

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