Development of a GC-376 Based Peptidomimetic PROTAC as a Degrader of 3-Chymotrypsin-like Protease of SARS-CoV-2 DOI
Deborah Grifagni, Elena Lenci, Alessia De Santis

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(2), P. 250 - 257

Published: Jan. 10, 2024

We have applied a proteolysis targeting chimera (PROTAC) technology to obtain peptidomimetic molecule able trigger the degradation of SARS-CoV-2 3-chymotrypsin-like protease (3CLPro). The PROTAC was designed by conjugating GC-376 based dipeptidyl 3CLPro ligand pomalidomide moiety through piperazine–piperidine linker. NMR and crystallographic data complemented with enzymatic cellular studies showed that (i) binds active site dimeric state forming reversible covalent bond sulfur atom catalytic Cys145, (ii) linker cereblon-ligand protrude from protein, displaying high degree flexibility no interactions other regions (iii) reduces protein levels in cultured cells. This study paves way for future applicability PROTACs tackle 3CLPro-dependent viral infections.

Language: Английский

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials DOI Creative Commons
Xin Xie, Tingting Yu, Xiang Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Language: Английский

Citations

175
An overview of PROTACs: a promising drug discovery paradigm DOI Creative Commons

Liu Zi,

Mingxing Hu,

Yang Yu

et al.

Molecular Biomedicine, Journal Year: 2022, Volume and Issue: 3(1)

Published: Dec. 20, 2022

Abstract Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets being studied, and most works focus on their enzymatic functions. Unlike small molecules, inhibit whole biological function binding to inducing subsequent proteasomal degradation. compensate for limitations transcription factors, nuclear proteins, other scaffolding difficult handle with traditional small-molecule inhibitors. have successfully degraded diverse such BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 ARV-471 exhibited excellent efficacy clinical II trials. However, what appropriate PROTAC achieve better benefits than inhibitors not fully understood. how rationally design an efficient optimize it be orally effective poses big challenges researchers. In this review, we summarize features technology, analyze detail general principles designing PROTACs, discuss typical application different categories. addition, also introduce progress relevant trial results representative assess may face. Collectively, our studies provide references further PROTACs.

Language: Английский

Citations

164
The roles of E3 ubiquitin ligases in cancer progression and targeted therapy DOI Creative Commons

Chibuzo Sampson,

Qiuping Wang,

Wuxiyar Otkur

et al.

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(3)

Published: March 1, 2023

Abstract Ubiquitination is one of the most important post‐translational modifications which plays a significant role in conserving homeostasis cellular proteins. In ubiquitination process, ubiquitin conjugated to target protein substrates for degradation, translocation or activation, dysregulation linked several diseases including various types cancers. E3 ligases are regarded as influential enzyme owing their ability select, bind and recruit ubiquitination. particular, pivotal cancer hallmarks pathways where they serve tumour promoters suppressors. The specificity coupled with implication engendered development compounds that specifically therapy. this review, we highlight such sustained proliferation via cell cycle progression, immune evasion promoting inflammation, apoptosis. addition, summarise application small treatment along significance targeting potential

Language: Английский

Citations

74
Annual review of PROTAC degraders as anticancer agents in 2022 DOI
Xiao Wang,

Zhao-Long Qin,

Na Li

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116166 - 116166

Published: Jan. 25, 2024

Language: Английский

Citations

59
Tracking the PROTAC degradation pathway in living cells highlights the importance of ternary complex measurement for PROTAC optimization DOI Creative Commons
Martin P. Schwalm, Andreas Krämer, Anja Dölle

et al.

Cell chemical biology, Journal Year: 2023, Volume and Issue: 30(7), P. 753 - 765.e8

Published: June 25, 2023

Language: Английский

Citations

51
Characteristic roadmap of linker governs the rational design of PROTACs DOI Creative Commons
Yawen Dong, Tingting Ma, Ting Xu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4266 - 4295

Published: April 11, 2024

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected linker. The linker plays pivotal role determining PROTAC's biodegradative efficacy. Advanced and rationally designed linkers are under development. Nonetheless, correlation between characteristics efficacy remains under-investigated. Consequently, this study will present multidisciplinary analysis of their impact on efficacy, thereby guiding rational design linkers. We primarily discuss structural types linkers, optimization strategies used design. Furthermore, we how factors like length, group type, flexibility, linkage site affect biodegradation efficiency PROTACs. believe that work contribute towards advancement research area.

Language: Английский

Citations

30
Targeting the undruggables—the power of protein degraders DOI Creative Commons
Chao Zhang, Yongbo Liu, Guangchen Li

et al.

Science Bulletin, Journal Year: 2024, Volume and Issue: 69(11), P. 1776 - 1797

Published: March 29, 2024

Undruggable targets typically refer to a class of therapeutic that are difficult target through conventional methods or have not yet been targeted, but great clinical significance. According statistics, over 80% disease-related pathogenic proteins cannot be targeted by current treatment methods. In recent years, with the advancement basic research and new technologies, development various technologies mechanisms has brought perspectives overcome challenging drug targets. Among them, protein degradation technology is breakthrough strategy for This can specifically identify directly degrade utilizing inherent pathways within cells. form includes types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting (AUTAC), (AUTOTAC), degrader-antibody conjugate (DAC). article systematically summarizes application in degraders Finally, looks forward future direction prospects technology.

Language: Английский

Citations

22
Targeting Arginine Methyltransferase PRMT5 for Cancer Therapy: Updated Progress and Novel Strategies DOI
Jiahong Zheng, Bang Li, Yingqi Wu

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(13), P. 8407 - 8427

Published: June 27, 2023

As a predominant type II protein arginine methyltransferase, PRMT5 plays critical roles in various normal cellular processes by catalyzing the mono- and symmetrical dimethylation of wide range histone nonhistone substrates. Clinical studies have revealed that high expression is observed different solid tumors hematological malignancies closely associated with cancer initiation progression. Accordingly, becoming promising anticancer target has received great attention both pharmaceutical industry academic community. In this Perspective, we comprehensively summarize recent advances development first-generation enzymatic inhibitors highlight novel strategies targeting past 5 years. We also discuss challenges opportunities inhibition, aim shedding light on future drug discovery.

Language: Английский

Citations

43
Nano Proteolysis Targeting Chimeras (PROTACs) with Anti‐Hook Effect for Tumor Therapy DOI

Ni‐Yuan Zhang,

Da‐Yong Hou, Xingjie Hu

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(37)

Published: July 24, 2023

Abstract Proteolysis targeting chimera (PROTAC) is an emerging pharmacological modality with innovated post‐translational protein degradation capabilities. However, off‐target induced unintended tissue effects and intrinsic “hook effect” hinder PROTAC biotechnology to be maturely developed. Herein, intracellular fabricated nano proteolysis chimeras (Nano‐PROTACs) a center‐spoke network for achieving efficient dose‐dependent in tumor reported. The precursors are triggered by higher GSH concentrations inside cells, which subsequently situ self‐assemble into Nano‐PROTACs through intermolecular hydrogen bond interactions. fibrous can form effective polynary complexes E3 ligases multi‐binding sites, “anti‐hook effect”. generality efficacy of validated degrading variable interest (POI) such as epidermal growth factor receptor (EGFR) androgen (AR) wide‐range manner 95 % rate long‐lasting potency up 72 h vitro. Significantly, achieve vivo 79 inhibition A549 LNCap xenograft mice models, respectively. Taking advantages self‐assembly strategy, the provide generalizable platform promote precise clinical translational application PROTAC.

Language: Английский

Citations

41
Targeted protein degradation in cancers: Orthodox PROTACs and beyond DOI Creative Commons
Jin Li, Xinxin Chen, Aiping Lü

et al.

The Innovation, Journal Year: 2023, Volume and Issue: 4(3), P. 100413 - 100413

Published: March 15, 2023

Targeted protein degradation (TPD) is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors. Proteolysis-targeting chimera (PROTAC) technology can be used target proteins by hijacking ubiquitin-proteasome system. Conceptually, PROTAC aims "undruggable" majority in human proteome. Through constant exploration and optimization PROTACs exploitation other TPD strategies over two decades, has expanded from theoretical studies clinical strategies, with practical applications oncological, immunological, diseases. In this review, we introduce mechanisms, features, molecular targets orthodox summarize drugs under study cancer therapeutics trials. We also discuss derivatives such lysosome-targeting chimeras, autophagy-targeting glue strategies. Collectively, summarized herein support full potential biomedical industry.

Language: Английский

Citations

37