Optimization of PROTAC Ternary Complex Using DNA Encoded Library Approach DOI Creative Commons
Qiuxia Chen, Chuan Liu, Wei Wang

et al.

ACS Chemical Biology, Journal Year: 2023, Volume and Issue: 18(1), P. 25 - 33

Published: Jan. 6, 2023

The proteolysis targeting chimera (PROTAC) strategy results in the down-regulation of unwanted protein(s) for disease treatment. In PROTAC process, a heterobifunctional degrader forms ternary complex with target protein interest (POI) and an E3 ligase, which ubiquitination proteasomal degradation POI. While formation is key attribute degraders, modification molecule to optimize can be labor-intensive tedious process. this study, we take advantage DNA-encoded library (DEL) technology efficiently synthesize vast number possible molecules describe parallel screening approach that utilizes DNA barcodes as reporters cooperative binding. We use designed DEL against BRD4 CRBN dual affinity selection method direct discovery novel, potent PROTACs importantly demonstrate clear SAR. Such evaluates all potential simultaneously, avoids interference solubility permeability, uses POI ligase proteins efficient manner.

Language: Английский

Current strategies for the design of PROTAC linkers: a critical review DOI Creative Commons
Robert I. Troup, Charlene Fallan, Matthias G. J. Baud

et al.

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

Citations

254
Proteolysis-targeting chimeras (PROTACs) in cancer therapy DOI Creative Commons
Xinyi Li, Wenchen Pu,

Qingquan Zheng

et al.

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: April 11, 2022

Abstract Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target and E3 ubiquitin ligase together to trigger proteasomal degradation of by the ubiquitin-proteasome system. has emerged as a promising approach therapy in various diseases, particularly cancers. In this review, we introduce principle development technology, well advantages PROTACs over traditional anti-cancer therapies. Moreover, summarize application targeting critical oncoproteins, provide guidelines molecular design discuss challenges PROTACs.

Language: Английский

Citations

188
PROTACs: great opportunities for academia and industry (an update from 2020 to 2021) DOI Creative Commons

Ming He,

Chao-Guo Cao, Zhihao Ni

et al.

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

Citations

174
Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges DOI
Shenxin Zeng,

Wenhai Huang,

Xiaoliang Zheng

et al.

European Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 210, P. 112981 - 112981

Published: Oct. 31, 2020

Language: Английский

Citations

166
Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation DOI Creative Commons
Michael J. Bond, Craig M. Crews

RSC Chemical Biology, Journal Year: 2021, Volume and Issue: 2(3), P. 725 - 742

Published: Jan. 1, 2021

With the discovery of PROteolysis TArgeting Chimeras (PROTACs) twenty years ago, targeted protein degradation (TPD) has changed landscape drug development.

Language: Английский

Citations

162
Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic DOI
Zhenyi Hu, Craig M. Crews

ChemBioChem, Journal Year: 2021, Volume and Issue: 23(2)

Published: Sept. 8, 2021

Abstract Proteolysis‐targeting chimeras (PROTACs), an emerging paradigm‐shifting technology, hijacks the ubiquitin‐proteasome system for targeted protein degradation. PROTACs induce ternary complexes between E3 ligase and POI, this induced proximity leads to polyUb chain formation on substrates eventual proteasomal‐mediated POI have shown great therapeutic potential by degrading many disease‐causing proteins, such as androgen receptor BRD4. The PROTAC technology has advanced significantly in last two decades, with repertoire of targets increased tremendously. Herein, we describe recent developments focusing mechanistic kinetic studies, pharmacokinetic study, spatiotemporal control PROTACs, covalent resistance new ligands.

Language: Английский

Citations

159
E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points DOI Creative Commons
Aleša Bricelj, Christian Steinebach, Robert D. Kuchta

et al.

Frontiers in Chemistry, Journal Year: 2021, Volume and Issue: 9

Published: July 5, 2021

Proteolysis-targeting chimeras (PROTACs) have received tremendous attention as a new and exciting class of therapeutic agents that promise to significantly impact drug discovery. These bifunctional molecules consist target binding unit, linker, an E3 ligase moiety. The chemically-induced formation ternary complexes leads ubiquitination proteasomal degradation proteins. Among the plethora ligases, only few been utilized for novel PROTAC technology. However, extensive knowledge on preparation ligands their utilization PROTACs has already acquired. This review provides in-depth analysis synthetic entries functionalized most relevant ligands, i.e. CRBN, VHL, IAP, MDM2. Less commonly used are also presented. We compare different preparative routes with respect feasibility productivity. A particular focus was set chemistry linker attachment by discussing opportunities connect ligand at appropriate exit vector assemble final PROTAC. comprehensive includes many facets involved in synthesis such complex is expected serve compendium support future attempts towards PROTACs.

Language: Английский

Citations

158
Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras DOI
Troy A. Bemis, James J. La Clair, Michael D. Burkart

et al.

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(12), P. 8042 - 8052

Published: June 9, 2021

A current bottleneck in the development of proteolysis targeting chimeras (PROTACs) is empirical nature linker length structure–activity relationships (SARs). multidisciplinary approach to alleviate detailed here. First, we examine four published synthetic approaches that have been developed increase throughput. We then discuss advances structural biology and computational chemistry led successful rational PROTAC design efforts give promise de novo silico. Lastly, present a model generated from curated list SARs studies normalized reflect how linear affects observed degradation potency (DC50).

Language: Английский

Citations

153
Target and tissue selectivity of PROTAC degraders DOI

Robert G. Guenette,

Seung Wook Yang, Jaeki Min

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(14), P. 5740 - 5756

Published: Jan. 1, 2022

In this review, we focus on recent progress towards making selective PROTAC molecules and new technologies that will continue to push the boundaries of achieving target tissue selectivity.

Language: Английский

Citations

150
From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation DOI Creative Commons
Carlotta Cecchini,

Sara Pannilunghi,

Sébastien Tardy

et al.

Frontiers in Chemistry, Journal Year: 2021, Volume and Issue: 9

Published: April 20, 2021

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the ubiquitin-proteasome system (UPS). This modality has emerged as an orthogonal approach to use of small-molecule inhibitors for knocking down classic targets and disease-related classified, until now, “undruggable.” In early 2019, first protein reached clinic, drawing attention PROTACs one most appealing technology in drug discovery landscape. Despite these promising results, often affected poor cellular permeability due their high molecular weight (MW) large exposed polar surface area (PSA). Herein, we report a comprehensive record PROTAC design, pharmacology thermodynamic challenges solutions, well some available strategies enhance uptake, including suggestions biological tools vitro evaluation toward successful degradation.

Language: Английский

Citations

126