Expanding the ligand spaces for E3 ligases for the design of protein degraders DOI Creative Commons
Rahman Shah Zaib Saleem, Martin P. Schwalm, Stefan Knapp

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 105, P. 117718 - 117718

Published: April 12, 2024

Targeted protein degradation (TPD) has recently emerged as an exciting new drug modality. However, the strategy of developing small molecule-based degraders evolved over past two decades and now established molecular tags that are already in clinical use, well chimeric molecules, PROteolysis TArgeting Chimeras (PROTACs), based mainly on ligand systems developed for E3 ligases CRBN VHL. The large size human ligase family suggests PROTACs can be by targeting a diversity ligases, some which have restricted expression patterns with potential to design disease- or tissue-specific degraders. Indeed, many ligands been published recently, confirming druggability ligases. This review summarises recent data highlights challenges these molecules into efficient rivalling degrader systems.

Language: Английский

Proteomic discovery of chemical probes that perturb protein complexes in human cells DOI Creative Commons
Michael R. Lazear, Jarrett R. Remsberg, Martin G. Jaeger

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(10), P. 1725 - 1742.e12

Published: April 20, 2023

Language: Английский

Citations

66
Recent Advances in Covalent Drug Discovery DOI Creative Commons
D. M. Schaefer, Xinlai Cheng

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(5), P. 663 - 663

Published: April 28, 2023

In spite of the increasing number biologics license applications, development covalent inhibitors is still a growing field within drug discovery. The successful approval some protein kinase inhibitors, such as ibrutinib (BTK inhibitor) and dacomitinib (EGFR inhibitor), very recent discovery for viral proteases, boceprevir, narlaprevir, nirmatrelvir, represent new milestone in development. Generally, formation bonds that target proteins can offer drugs diverse advantages terms selectivity, resistance, administration concentration. most important factor electrophile (warhead), which dictates reactivity, type binding (i.e., reversible or irreversible) be modified/optimized through rational designs. Furthermore, are becoming more common proteolysis, targeting chimeras (PROTACs) degrading proteins, including those currently considered to ‘undruggable’. aim this review highlight current state inhibitor development, short historical overview examples applications PROTAC technologies treatment SARS-CoV-2 virus.

Language: Английский

Citations

45
Discovery of Nanomolar DCAF1 Small Molecule Ligands DOI Creative Commons
Alice Shi Ming Li, Serah Kimani,

Brian J. Wilson

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(7), P. 5041 - 5060

Published: March 22, 2023

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4DCAF1 and EDVP), plays critical physiological role in protein degradation, considered drug target for various cancers. Antagonists could be used toward the development therapeutics cancers viral treatments. We WDR domain to screen 114-billion-compound DNA encoded library (DEL) identified candidate compounds using similarity search machine learning. This led discovery compound (Z1391232269) with an SPR KD 11 μM. Structure-guided hit optimization OICR-8268 (26e) 38 nM cellular engagement EC50 10 μM as measured by thermal shift assay (CETSA). excellent tool enable next-generation ligands cancer therapeutics, further investigation functions cells, DCAF1-based PROTACs.

Language: Английский

Citations

44
DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance DOI Creative Commons
Martin Schröder, Martin Renatus,

Xiaoyou Liang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 4, 2024

Targeted protein degradation (TPD) mediates level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only few have been utilized TPD. Interestingly, the workhorse ligase CRBN observed be downregulated settings resistance immunomodulatory inhibitory drugs (IMiDs). Here we show that essential receptor DCAF1 can harnessed utilizing selective, non-covalent binder. We confirm this binder functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical genetic rescue experiments validate specific via CRL4

Language: Английский

Citations

39
Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1 DOI

Margot Meyers,

Sabine Cismoski,

Anoohya Panidapu

et al.

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(1), P. 58 - 68

Published: Jan. 9, 2024

Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional proteolysis targeting chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such cereblon and VHL. However, previous studies surprisingly uncovered molecular glue degraders that exploit CUL4 adaptor DDB1 to degrade neosubstrate Here, we sought investigate whether can be discovered exploited PROTAC applications. We activity-based profiling cysteine chemoproteomic screening identify covalent recruiter targets C173 on this develop PROTACs BRD4 androgen receptor (AR). demonstrated the results in selective short isoform over long proteasome, NEDDylation, DDB1-dependent manner. also AR with prostate cancer cells. Our study approaches used discover adapter proteins these applications neo-substrates.

Language: Английский

Citations

19
Targeted protein degradation: advances in drug discovery and clinical practice DOI Creative Commons
Guangcai Zhong, Xiaoyu Chang, Weilin Xie

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 6, 2024

Abstract Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing stark contrast to traditional approaches like small molecule inhibitors that primarily focus on inhibiting function. This advanced technology capitalizes the cell’s intrinsic proteolytic systems, including proteasome and lysosomal pathways, selectively eliminate disease-causing proteins. TPD not only enhances efficacy of treatments but also expands scope applications. Despite its considerable potential, faces challenges related properties drugs their rational design. review thoroughly explores mechanisms clinical advancements TPD, from initial conceptualization practical implementation, with particular proteolysis-targeting chimeras molecular glues. In addition, delves into emerging technologies methodologies aimed at addressing these enhancing efficacy. We discuss significant trials highlight promising outcomes associated drugs, illustrating potential transform treatment landscape. Furthermore, considers benefits combining other therapies enhance overall effectiveness overcome drug resistance. The future directions applications are explored, presenting an optimistic perspective further innovations. By offering comprehensive overview current innovations faced, this assesses transformative revolutionizing development setting stage for new era medical therapy.

Language: Английский

Citations

19
Proteomic Ligandability Maps of Spirocycle Acrylamide Stereoprobes Identify Covalent ERCC3 Degraders DOI
Zhonglin Liu, Jarrett R. Remsberg,

Haoxin Li

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(15), P. 10393 - 10406

Published: April 3, 2024

Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe set of stereo- and regiochemically defined spirocycle acrylamides the analysis these electrophilic "stereoprobes" human cancer cells by cysteine-directed ABPP. Despite showing attenuated reactivity compared structurally related azetidine acrylamide stereoprobes, preferentially liganded specific cysteines on diverse classes. One compound termed ZL-12A promoted degradation TFIIH helicase ERCC3. Interestingly, reacts same cysteine (C342) ERCC3 as natural product triptolide, which did not lead but instead causes collateral loss RNA polymerases. triptolide cross-antagonized one another's profiles. Finally, provide evidence that antihypertension drug spironolactone─previously found promote through an enigmatic mechanism─also ERCC3_C342. Our findings thus monofunctional degraders highlight how covalent targeting can produce strikingly different functional outcomes.

Language: Английский

Citations

16
Proteomics: An In‐Depth Review on Recent Technical Advances and Their Applications in Biomedicine DOI Open Access
Jing Liang, Jun Tian,

Huadong Zhang

et al.

Medicinal Research Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

ABSTRACT Proteins hold pivotal importance since many diseases manifest changes in protein activity. Proteomics techniques provide a comprehensive exploration of structure, abundance, and function biological samples, enabling the holistic characterization overall organisms. Nowadays, breadth emerging methodologies proteomics is unprecedentedly vast, with constant optimization technologies sample processing, data collection, analysis, its scope application steadily transitioning from bench to clinic. Here, we offer an insightful review technical developments applications biomedicine over past 5 years. We focus on profound contributions profiling disease spectra, discovering new biomarkers, identifying promising drug targets, deciphering alterations conformation, unearthing protein–protein interactions. Moreover, summarize cutting‐edge potential breakthroughs pipeline principal challenges proteomics. Based these, aspire broaden applicability inspire researchers enhance our understanding complex systems by utilizing such techniques.

Language: Английский

Citations

2
Targeted Protein Degradation through E2 Recruitment DOI Creative Commons
Nafsika Forte, Dustin Dovala, Matthew J. Hesse

et al.

ACS Chemical Biology, Journal Year: 2023, Volume and Issue: 18(4), P. 897 - 904

Published: March 20, 2023

Targeted protein degradation (TPD) with proteolysis targeting chimeras (PROTACs), heterobifunctional compounds consisting of ligands linked to recruiters E3 ubiquitin ligases, has arisen as a powerful therapeutic modality induce the proximity target proteins ligases ubiquitinate and degrade specific in cells. Thus far, PROTACs have primarily exploited recruitment or their substrate adapter but not more core components ubiquitin-proteasome system (UPS). In this study, we used covalent chemoproteomic approaches discover recruiter against E2 conjugating enzyme UBE2D─EN67─that targets an allosteric cysteine, C111, without affecting enzymatic activity protein. We demonstrated that UBE2D could be degraders neo-substrate UBE2D-dependent manner, including BRD4 androgen receptor. Overall, our data highlight potential for UPS machinery, such enzymes, TPD, underscore utility strategies identifying novel additional UPS.

Language: Английский

Citations

36
Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes DOI
Ying Chen, Gregory B. Craven, Roarke A. Kamber

et al.

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(11), P. 1616 - 1625

Published: July 17, 2023

Language: Английский

Citations

32