Open Access

Exploration of Targeted Anti-tumor Therapy, volume 1, issue 5

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

Robert I Troup ¹

Charlene Fallan ²

M G J Baud ¹

Hide authors affiliations Show authors affiliations: 2 affiliations

School of Chemistry, University of Southampton, Highfield, SO17 1BJ Southampton, UK |

Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge Science Park, Milton Road, CB4 0WG Cambridge, UK |

Publication type: Journal Article

Publication date: 2020-10-11

Open Exploration Publishing

Journal: Exploration of Targeted Anti-tumor Therapy

Quartile SCImago

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Quartile WOS

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Impact factor: —

ISSN: 26923114

DOI: 10.37349/etat.2020.00018

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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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Troup R. I., Fallan C., Baud M. G. J. Current strategies for the design of PROTAC linkers: a critical review // Exploration of Targeted Anti-tumor Therapy. 2020. Vol. 1. No. 5.

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Troup R. I., Fallan C., Baud M. G. J. Current strategies for the design of PROTAC linkers: a critical review // Exploration of Targeted Anti-tumor Therapy. 2020. Vol. 1. No. 5.

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RIS Copy

TY - JOUR

DO - 10.37349/etat.2020.00018

UR - https://www.explorationpub.com/Journals/etat/Article/100218

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

T2 - Exploration of Targeted Anti-tumor Therapy

AU - Troup, Robert I

AU - Fallan, Charlene

AU - Baud, M G J

PY - 2020

DA - 2020/10/11 00:00:00

PB - Open Exploration Publishing

IS - 5

VL - 1

SN - 2692-3114

ER -

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@article{2020_Troup,

author = {Robert I Troup and Charlene Fallan and M G J Baud},

title = {Current strategies for the design of PROTAC linkers: a critical review},

journal = {Exploration of Targeted Anti-tumor Therapy},

year = {2020},

volume = {1},

publisher = {Open Exploration Publishing},

month = {oct},

url = {https://www.explorationpub.com/Journals/etat/Article/100218},

number = {5},

doi = {10.37349/etat.2020.00018}

}

Found error?

Publisher

Open Exploration Publishing

Journal

Exploration of Targeted Anti-tumor Therapy

Quartile SCImago

—

Quartile WOS

—

Impact factor

—

ISSN

26923114 (Electronic)