PHOTACs Enable Optical Control of Protein Degradation

31 May 2019, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

PROTAC
Targeted Protein Degradation
BRD2
BRD3
BRD4
FKBP12
cereblon E 3 ubiquitin ligase
Thalidomide
photopharmacology
azobenzene
Photoswitch
Photodynamic Therapy
Cereblon

Supplementary materials

Title
Description
Actions
Title
Photac SI Submitted 5-30-19
Description
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