Current strategies for the design of PROTAC linkers: a critical review.
PROTAC
linker design
protein degradation
Journal
Exploration of targeted anti-tumor therapy
ISSN: 2692-3114
Titre abrégé: Explor Target Antitumor Ther
Pays: United States
ID NLM: 101770662
Informations de publication
Date de publication:
2020
2020
Historique:
received:
01
07
2020
accepted:
23
08
2020
entrez:
1
9
2022
pubmed:
1
1
2020
medline:
1
1
2020
Statut:
ppublish
Résumé
PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an "anchor" to bind to an E3 ubiquitin ligase and a "warhead" to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional "trial and error" approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design.
Identifiants
pubmed: 36046485
doi: 10.37349/etat.2020.00018
pii: etat-01-100218
pmc: PMC9400730
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
273-312Informations de copyright
© The Author(s) 2020.
Déclaration de conflit d'intérêts
The authors declare that they have no conflicts of interest.
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