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Current strategies for the design of PROTAC linkers: a critical review

Current strategies for the design of PROTAC linkers: a critical review
Current strategies for the design of PROTAC linkers: a critical review
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.
PROTAC, protein degradation, linker design
2692-3114
273-312
Troup, Robert Ian
4e5eae00-ac0a-44a4-8c32-1042d6261c46
Fallan, Charlene
2753821a-35b7-4cbf-851d-9a3a8929af2b
Baud, Matthias G.J.
8752d519-3d33-43b6-9a77-ab731d410c2e
Troup, Robert Ian
4e5eae00-ac0a-44a4-8c32-1042d6261c46
Fallan, Charlene
2753821a-35b7-4cbf-851d-9a3a8929af2b
Baud, Matthias G.J.
8752d519-3d33-43b6-9a77-ab731d410c2e

Troup, Robert Ian, Fallan, Charlene and Baud, Matthias G.J. (2020) Current strategies for the design of PROTAC linkers: a critical review. Exploration of Targeted Anti-Tumor Therapy, 1, 273-312. (doi:10.37349/etat.2020.00018).

Record type: Review

Abstract

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.

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Accepted/In Press date: 23 August 2020
e-pub ahead of print date: 30 October 2020
Keywords: PROTAC, protein degradation, linker design

Identifiers

Local EPrints ID: 444970
URI: http://eprints.soton.ac.uk/id/eprint/444970
ISSN: 2692-3114
PURE UUID: f68c8930-b801-41c7-a5f6-74c46672886e
ORCID for Matthias G.J. Baud: ORCID iD orcid.org/0000-0003-3714-4350

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Date deposited: 13 Nov 2020 17:31
Last modified: 18 Feb 2021 17:26

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Author: Robert Ian Troup
Author: Charlene Fallan

University divisions

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