Advancing targeted protein degradation for cancer therapy

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 21(10), P. 638 - 654

Published: June 15, 2021

Language: Английский

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PROTACs: past, present and future

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(12), P. 5214 - 5236

Published: Jan. 1, 2022

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of one ligand that binds to a protein interest (POI) and another can recruit an E3 ubiquitin ligase. The chemically-induced proximity between the POI ligase results in ubiquitination subsequent degradation by ubiquitin-proteasome system (UPS). event-driven mechanism action (MOA) PROTACs offers several advantages compared traditional occupancy-driven small molecule inhibitors, such as catalytic nature, reduced dosing frequency, more potent longer-lasting effect, added layer selectivity reduce potential toxicity, efficacy face drug-resistance mechanisms, targeting nonenzymatic functions, expanded target space. Here, we highlight important milestones briefly discuss lessons learned about targeted (TPD) recent years conjecture on efforts still needed expand toolbox for PROTAC discovery ultimately provide promising therapeutics.

Language: Английский

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Targeted protein degradation: mechanisms, strategies and application

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: April 4, 2022

Abstract Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application activity modulators, particularly inhibitors, has been the mainstream in development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology emerged as one most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. addition PROTAC, many different targeted degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), Antibody-based PROTAC (AbTAC), are emerging. These technologies have only greatly expanded scope TPD, also provided fresh insights into discovery. Here, we summarize advances major TPD technologies, discuss their potential applications, hope provide a prime for both biologists chemists who interested this vibrant field.

Language: Английский

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

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2020, Volume and Issue: 1(5)

Published: Oct. 11, 2020

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind E3 ubiquitin ligase and a “warhead” protein interest, connected by chemical linker. Targeted degradation PROTACs has emerged as new modality for the knock down range proteins, with first agents now reaching clinical evaluation. It become increasingly clear that length composition linker play critical roles on physicochemical properties bioactivity PROTACs. While design historically received limited attention, PROTAC field is evolving rapidly currently undergoing important shift from synthetically tractable alkyl polyethylene glycol more sophisticated functional linkers. This promises unlock wealth novel enhanced therapeutic intervention. Here, authors provide timely overview diverse classes in published literature, along their underlying principles overall influence associated Finally, analysis current strategies assembly. The highlight limitations traditional “trial error” approach around selection, suggest potential future avenues further inform rational accelerate identification optimised In particular, believe advances computational structural methods will essential role gain better understanding structure dynamics ternary complexes, be address gaps knowledge design.

Language: Английский

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PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: May 7, 2021

Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through ubiquitin-proteasome system (UPS) to achieve effect on tumor growth. A number of literature studies PROTAC have proved insight into feasibility degrade proteins. Additionally, first oral PROTACs (ARV-110 and ARV-471) shown encouraging results clinical trials for prostate breast cancer treatment, which inspires a greater enthusiasm research. Here we focus structures mechanisms describe several classes degraders based E3 ligases.

Language: Английский

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Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 296, P. 100647 - 100647

Published: Jan. 1, 2021

Of late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool therapeutic modality. By co-opting pathways, TPD facilitates complete removal of the molecules from within or outside cell. While pioneering Proteolysis-Targeting Chimera (PROTAC) technology molecular glues hijack ubiquitin-proteasome system, newer modalities co-opt autophagy endo-lysosomal pathway. Using this mechanism, is posited to largely expand druggable space far beyond small-molecule inhibitors. In review, we discuss major advances in TPD, highlight our current understanding, explore outstanding questions field.

Language: Английский

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Protein arginine methyltransferases: promising targets for cancer therapy

Experimental & Molecular Medicine, Journal Year: 2021, Volume and Issue: 53(5), P. 788 - 808

Published: May 1, 2021

Abstract Protein methylation, a post-translational modification (PTM), is observed in wide variety of cell types from prokaryotes to eukaryotes. With recent and rapid advancements epigenetic research, the importance protein methylation has been highlighted. The histone proteins that contributes code not only dynamic but also finely controlled by methyltransferases demethylases, which are essential for transcriptional regulation genes. In addition, many nonhistone methylated, these modifications govern cellular functions, including RNA processing, translation, signal transduction, DNA damage response, cycle. Recently, arginine especially cycle repair processes, noted. Since dysregulation closely associated with cancer development, (PRMTs) have garnered significant interest as novel targets anticancer drug development. Indeed, several PRMT inhibitors phase 1/2 clinical trials. this review, we discuss biological functions PRMTs current development status therapy.

Language: Английский

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The PROTACtable genome

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(10), P. 789 - 797

Published: July 20, 2021

Language: Английский

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PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 9, 2022

Abstract PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such cancer, immune disorders, viral infections, neurodegenerative diseases, but also provide unique chemical knockdown tools biological research catalytic, reversible, rapid manner. In 2019, our group published review article “PROTACs: great opportunities academia industry” journal, summarizing representative compounds reported before end 2019. past 2 years, entire field protein experienced development, including large increase number papers on small-molecule degraders have entered will enter stage. addition PROTAC molecular glue technology, other technologies are developing rapidly. this article, we mainly summarize related targets 2020–2021 present researchers exciting developments degradation. The problems need solved briefly introduced.

Language: Английский

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Chemistries of bifunctional PROTAC degraders

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(16), P. 7066 - 7114

Published: Jan. 1, 2022

Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins.

Language: Английский

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