Proteomic approaches advancing targeted protein degradation

Gajanan Sathe; Gopal P. Sapkota

doi:10.1016/j.tips.2023.08.007

Proteomic approaches advancing targeted protein degradation

Gajanan Sathe (Lead / Corresponding author), Gopal P. Sapkota (Lead / Corresponding author)

MRC PPU

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Abstract

Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) and molecular glue (MG) degraders (MGDs) represent the most advanced TPD approaches, with some already used in clinical settings. Despite these advances, TPD still faces many challenges, pertaining to both the development of effective, selective, and tissue-penetrant degraders and understanding their mode of action. In this review, we focus on progress made in addressing these challenges. In particular, we discuss the utility and application of recent proteomic approaches as indispensable tools to enable insights into degrader development, including target engagement, degradation selectivity, efficacy, safety, and mode of action.

Original language	English
Pages (from-to)	786-801
Number of pages	16
Journal	Trends in Pharmacological Sciences
Volume	44
Issue number	11
Early online date	29 Sept 2023
DOIs	https://doi.org/10.1016/j.tips.2023.08.007
Publication status	Published - Nov 2023

Keywords

Targeted protein degradation
PROTAC
Molecular glue
Proteomics
Chemoproteomics
chemoproteomics
proteomics
targeted protein degradation
molecular glue

ASJC Scopus subject areas

Toxicology
Pharmacology

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Cite this

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abstract = "Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) and molecular glue (MG) degraders (MGDs) represent the most advanced TPD approaches, with some already used in clinical settings. Despite these advances, TPD still faces many challenges, pertaining to both the development of effective, selective, and tissue-penetrant degraders and understanding their mode of action. In this review, we focus on progress made in addressing these challenges. In particular, we discuss the utility and application of recent proteomic approaches as indispensable tools to enable insights into degrader development, including target engagement, degradation selectivity, efficacy, safety, and mode of action.",

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AB - Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) and molecular glue (MG) degraders (MGDs) represent the most advanced TPD approaches, with some already used in clinical settings. Despite these advances, TPD still faces many challenges, pertaining to both the development of effective, selective, and tissue-penetrant degraders and understanding their mode of action. In this review, we focus on progress made in addressing these challenges. In particular, we discuss the utility and application of recent proteomic approaches as indispensable tools to enable insights into degrader development, including target engagement, degradation selectivity, efficacy, safety, and mode of action.

KW - Targeted protein degradation

KW - PROTAC

KW - Molecular glue

KW - Proteomics

KW - Chemoproteomics

KW - chemoproteomics

KW - proteomics

KW - targeted protein degradation

KW - molecular glue

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DO - 10.1016/j.tips.2023.08.007

M3 - Article

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JO - Trends in Pharmacological Sciences

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Proteomic approaches advancing targeted protein degradation

Abstract

Keywords

ASJC Scopus subject areas

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