Photoactive bifunctional degraders: precision tools to regulate protein stability.
File(s)
Author(s)
Kounde, Cyrille S
Tate, Edward W
Type
Journal Article
Abstract
Targeted protein degradation with bifunctional degraders is positioned as a remarkable game-changing strategy to control cellular protein levels and promises a new therapeutic modality in drug discovery. Light activation of a degrader to achieve exquisite spatiotemporal control over protein stability in cells has attracted the interest of multiple research groups, with recent reports demonstrating optical control of proteolysis with chimeric molecules bearing photolabile or photoswitchable motifs. In this context of targeted proteolysis research spurring the emergence of innovative tools, we examine the design, synthesis, and properties of light-activated degraders. The significant impact of this approach in regulating disease-relevant protein levels in a light-dependent manner is highlighted with key examples, and future developments to fully harness the potential of light-induced protein degradation with photoactive bifunctional molecules are discussed.
Date Issued
2020-12-24
Date Acceptance
2020-11-01
Citation
Journal of Medicinal Chemistry, 2020, 63 (24), pp.15483-15493
ISSN
0022-2623
Publisher
American Chemical Society
Start Page
15483
End Page
15493
Journal / Book Title
Journal of Medicinal Chemistry
Volume
63
Issue
24
Copyright Statement
© 2020 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in ournal of Medicinal Chemistry, after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.0c01542
Sponsor
Engineering and Physical Sciences Research Council
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33226810
Grant Number
EP/R512540/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
E3 UBIQUITIN LIGASE
TARGETING CHIMERAS PROTACS
SPATIOTEMPORAL CONTROL
SMALL MOLECULES
DRUG DISCOVERY
DEGRADATION
PROTEOLYSIS
COMPLEX
DESIGN
Animals
Azo Compounds
Cell Cycle Proteins
Cell Proliferation
Drug Design
HeLa Cells
Humans
Light
Proteasome Endopeptidase Complex
Protein Stability
Proteins
Proteolysis
Small Molecule Libraries
Transcription Factors
Ubiquitin-Protein Ligases
Zebrafish
Zebrafish Proteins
Hela Cells
Animals
Zebrafish
Humans
Azo Compounds
Proteasome Endopeptidase Complex
Ubiquitin-Protein Ligases
Proteins
Cell Cycle Proteins
Zebrafish Proteins
Transcription Factors
Cell Proliferation
Drug Design
Light
Small Molecule Libraries
Protein Stability
Proteolysis
0304 Medicinal and Biomolecular Chemistry
0305 Organic Chemistry
1115 Pharmacology and Pharmaceutical Sciences
Medicinal & Biomolecular Chemistry
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-11-23