Precise Modulation of Protein Degradation by Smart PROTACs DOI

Junfei Cheng,

Guoqiang Dong, Wei Wang

et al.

ChemBioChem, Journal Year: 2024, Volume and Issue: 26(1)

Published: Oct. 5, 2024

Abstract Proteolysis‐targeting chimera (PROTAC) has emerged as an attractive therapeutic modality in drug discovery. PROTACs are bifunctional molecules that effectively bridge proteins of interest (POIs) with E3 ubiquitin ligases, such that, the target tagged and subsequently degraded via proteasome. Despite significant progress field targeted protein degradation (TPD), application conventional PROTAC degraders still faces challenges, including systemic toxicity induced by non‐tissue‐specific targeting. To address this issue, a variety smart can be activated specific stimuli, have been developed for achieving conditional spatiotemporal modulation levels. Here, on basis our contributions, we overview recent advances PROTACs, tumor microenvironment‐, photo‐, X‐ray radiation‐responsive enable controllable TPD. The design strategy, case studies, potential applications challenges will focused on.

Language: Английский

Emerging prodrug and nano-drug delivery strategies for the detection and elimination of senescent tumor cells DOI
Tao Wang,

Xianbao Shi,

Xiaolong Xu

et al.

Biomaterials, Journal Year: 2025, Volume and Issue: unknown, P. 123129 - 123129

Published: Jan. 1, 2025

Language: Английский

Citations

3
PROTACs coupled with oligonucleotides to tackle the undruggable DOI
Guangshuai Zhang,

Si Yan,

Yan Liu

et al.

Bioanalysis, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 16

Published: Feb. 3, 2025

Undruggable targets account for roughly 85% of human disease-related and represent a category therapeutic that are difficult to tackle with traditional methods, but their considerable clinical importance. These generally defined by planar functional interfaces the absence efficient ligand-binding pockets, making them unattainable conventional pharmaceutical strategies. The advent oligonucleotide-based proteolysis-targeting chimeras (PROTACs) has instilled renewed optimism in addressing these challenges. PROTACs facilitate targeted degradation undruggable entities, including transcription factors (TFs) RNA-binding proteins (RBPs), via proteasome-dependent mechanisms, thereby presenting novel approaches diseases linked targets. This review offers an in-depth examination recent progress integration PROTAC technology oligonucleotides target traditionally proteins, emphasizing design principles mechanisms action innovative PROTACs.

Language: Английский

Citations

2
Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions DOI Creative Commons
Rajamanikkam Kamaraj, Subhrojyoti Ghosh,

Souvadra Das

et al.

Bioconjugate Chemistry, Journal Year: 2024, Volume and Issue: 35(8), P. 1089 - 1115

Published: July 11, 2024

Targeted protein degradation or TPD, is rapidly emerging as a treatment that utilizes small molecules to degrade proteins cause diseases. TPD allows for the selective removal of disease-causing proteins, including proteasome-mediated degradation, lysosome-mediated and autophagy-mediated degradation. This approach has shown great promise in preclinical studies now being translated treat numerous diseases, neurodegenerative infectious cancer. review discusses latest advances its potential new chemical modality immunotherapy, with special focus on innovative applications cutting-edge research PROTACs (Proteolysis TArgeting Chimeras) their efficient translation from scientific discovery technological achievements. Our also addresses significant obstacles prospects this domain, while offering insights into future immunotherapeutic applications.

Language: Английский

Citations

6
Powering up targeted protein degradation through active and passive tumour-targeting strategies: Current and future scopes DOI
Janarthanan Venkatesan, Dhanashree Murugan,

Kalaiarasu Lakshminarayanan

et al.

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 263, P. 108725 - 108725

Published: Sept. 24, 2024

Language: Английский

Citations

4
CRBN‐PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications DOI Open Access
Riya Thapa, Asif Ahmad Bhat, Gaurav Gupta

et al.

Chemical Biology & Drug Design, Journal Year: 2024, Volume and Issue: 104(5)

Published: Nov. 1, 2024

Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as therapeutic target in cancer. CRBN regulates degradation various proteins cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are novel approach that uses cell's system to remove disease-causing selectively. CRBN-dependent work by tagging harmful for destruction through ubiquitin-proteasome system. This strategy offers several advantages over traditional protein inhibition methods, potential overcome drug resistance. Recent progress developing CRBN-based shown promising preclinical results both hematologic malignancies solid tumors. Additionally, have enhanced our understanding CRBN's role cancer, potentially serving biomarkers patient stratification predicting responses. In this review, we delineate mechanisms action (CRBN-PROTACs), summarize recent advances clinical applications, provide perspective on future development.

Language: Английский

Citations

4
DNA Tetrahedron-Driven Multivalent Proteolysis-Targeting Chimeras: Enhancing Protein Degradation Efficiency and Tumor Targeting DOI
Shiqing Li, Tao Zeng, Zhixing Wu

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Proteolysis-targeting chimeras (PROTACs) are dual-functional molecules composed of a protein interest (POI) ligand and an E3 ligase connected by linker, which can recruit POI ligases simultaneously, thereby inducing the degradation showing great potential in disease treatment. A challenge developing PROTACs is design linkers modification ligands to establish multifunctional platform that enhances efficiency antitumor activity. As programmable modifiable nanomaterial, DNA tetrahedron precisely assemble selectively recognize flexibly adjust distance between molecules, making them ideal linkers. Herein, we developed multivalent PROTAC based on tetrahedron, named AS-TD2-PRO. Using as combined modules targeting tumor cells, recognizing ligases, multiple together. We took undruggable target signal transducer activator transcription 3 (STAT3), associated with etiology progression variety malignant tumors, example this study. AS-TD2-PRO two STAT3 recognition demonstrated good enhancing tumor-specific compared traditional bivalent PROTACs. Furthermore, mouse model, superior therapeutic activity was observed. Overall, tetrahedron-driven both serve proof principle for introduce promising avenue cancer treatment strategies.

Language: Английский

Citations

0
Advancing brain tumor therapy: unveiling the potential of PROTACs for targeted protein degradation DOI

S.M. Ibrahim,

Muhammad Umer Khan, Saadia Noreen

et al.

Cytotechnology, Journal Year: 2025, Volume and Issue: 77(2)

Published: Jan. 31, 2025

Language: Английский

Citations

0
Prodrug Approach as a Strategy to Enhance Drug Permeability DOI Creative Commons
Mariana Moraes Dionysio de Souza, Ana Luísa Rodriguez Gini,

Jhonnathan Alves Moura

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(3), P. 297 - 297

Published: Feb. 21, 2025

Absorption and permeability are critical physicochemical parameters that must be balanced to achieve optimal drug uptake. These key factors closely linked the maximum absorbable dose required provide appropriate plasma levels of drugs. Among various strategies employed enhance solubility permeability, prodrug design stands out as a highly effective versatile approach for improving properties enabling optimization biopharmaceutical pharmacokinetic while mitigating adverse effects. Prodrugs compounds with reduced or no activity that, through bio-reversible chemical enzymatic processes, release an active parental drug. The application this technology has led significant advancements in during phase, it offers broad potential further development. Notably, approximately 13% drugs approved by U.S. Food Drug Administration (FDA) between 2012 2022 were prodrugs. In review article, we will explore describing examples market We also describe use optimize PROteolysis TArgeting Chimeras (PROTACs) using conjugation technologies. highlight some new technologies prodrugs enrich properties, contributing developing safe

Language: Английский

Citations

0
Cascade-responsive nano-PROTACs for tumor-specific ALK protein degradation and enhanced cancer therapy DOI
Yanping Zhao,

Junhui Sui,

Jian Chang

et al.

Nano Today, Journal Year: 2025, Volume and Issue: 62, P. 102693 - 102693

Published: Feb. 26, 2025

Language: Английский

Citations

0
Targeted Degradation of ZBP1 with Covalent PROTACs for Anti‐Inflammatory Treatment of Infections DOI Open Access
Riming Huang,

Yusi Hu,

Yifan Wang

et al.

Angewandte Chemie International Edition, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Z-DNA binding protein 1 (ZBP1) has emerged as a critical pathogen-sensing that upon activation, triggers necroptotic signaling cascades, leading to potent inflammatory response and potentially causing significant tissue damage. However, available drugs specifically developed for the effective inhibition or degradation of ZBP1 is still lacking so far. In this study, we covalent recognition-based PROTAC (C-PROTAC) molecule ZBP1. It consists DNA aptamer recognition moiety an E3 enzyme-recruiting unit, connected by linker containing N-acyl-N-alkyl sulfonamides (NASA) groups. The binds ZBP1, while NASA-containing facilitates formation bond between target protein. ligase-recruiting unit then directs ubiquitin-proteasome system degrade ZBP1-PROTAC complex. This approach combines high specificity aptamers with efficiency degradation-inducing capabilities PROTACs, providing powerful tool targeted degradation. successful application technology highlights its potential selective elimination disease-associated proteins development novel therapeutic strategies.

Language: Английский

Citations

0