PHOTACs enable optical control of protein degradation.
Sci Adv
; 6(8): eaay5064, 2020 02.
Article
in En
| MEDLINE
| ID: mdl-32128406
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.
Full text:
1
Database:
MEDLINE
Main subject:
Optical Phenomena
/
Proteolysis
Limits:
Humans
Language:
En
Journal:
Sci Adv
Year:
2020
Type:
Article
Affiliation country:
United States