Precision-engineered PROTACs minimize off-tissue effects in cancer therapy DOI Creative Commons

Jianghua Shi,

Luo Wang,

Xuanwei Zeng

и другие.

Frontiers in Molecular Biosciences, Год журнала: 2024, Номер 11

Опубликована: Ноя. 22, 2024

Proteolysis-targeting chimeras (PROTACs) offer a groundbreaking approach to selectively degrade disease-related proteins by utilizing the ubiquitin-proteasome system. While this strategy shows great potential in preclinical and clinical settings, off-tissue effects remain major challenge, leading toxicity healthy tissues. This review explores recent advancements aimed at improving PROTAC specificity, including tumor-specific ligand-directed PROTACs, pro-PROTACs activated tumor environments, E3 ligase overexpression strategies. Innovations such as PEGylation nanotechnology also play role optimizing efficacy. These developments hold promise for safer, more effective cancer therapies, though challenges translation.

Язык: Английский

PROTAC technology: From drug development to probe technology for target deconvolution DOI

Si Yan,

Guangshuai Zhang,

Wei Luo

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 276, С. 116725 - 116725

Опубликована: Июль 30, 2024

Язык: Английский

Процитировано

19
Targeted degradation of membrane and extracellular proteins with LYTACs DOI

Yuyang Li,

Yang Yang, Renshuai Zhang

и другие.

Acta Pharmacologica Sinica, Год журнала: 2024, Номер unknown

Опубликована: Авг. 5, 2024

Язык: Английский

Процитировано

6
Integrating Proteolysis‐Targeting Chimeras (PROTACs) with Delivery Systems for More Efficient and Precise Targeted Protein Degradation DOI

Jiachan Lin,

Zirui Chen, Dan Zhang

и другие.

Macromolecular Rapid Communications, Год журнала: 2025, Номер unknown

Опубликована: Апрель 4, 2025

Targeted protein degradation (TPD) using the proteolysis-targeting chimeras (PROTACs) is emerging as a revolutionary technology, offering potential strategy for cancer treatment by inducing of overexpressed oncogenic proteins in tumors. PROTACs function recruiting E3 ligases and utilizing ubiquitin-proteasome pathway (UPS) to catalyze target proteins. Compared traditional small molecules inhibitors, exhibit enhanced selectivity, ability overcome drug resistance, traditionally deemed "undruggable". However, poor water solubility low cellular permeability significantly limit their pharmacokinetic properties, while systemic toxicity may hinder clinical application. To address these limitations, strategies that integrate with delivery systems are gaining attention. This review summarizes latest advancements various enhance vivo efficacy reduce off-target effects PROTACs, including prototype nanoparticles, covalent modification-based prodrug strategies, innovative multi-headed designs, microneedle systems, discussing design principles associated challenges. The combination potent multifunctional holds promise accelerating translation improving therapeutic treatment.

Язык: Английский

Процитировано

0
Transforming Therapeutic Approaches with PROTAC Technology: New Targets and Potentials DOI Creative Commons
Robert B. Kargbo

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(5), С. 573 - 575

Опубликована: Апрель 26, 2024

This Patent Highlight delves into the ground-breaking impact of Proteolysis Targeting Chimeras (PROTACs) on targeted protein degradation, offering novel strategies to eliminate pathogenic proteins. By exploring cutting-edge development compounds targeting IRAK-4 and CDK2, this work illuminates PROTACs' role in treating immune disorders cancer. The analysis not only highlights specificity potential PROTACs transforming disease treatment but also addresses challenges future directions technology, emphasizing its broad applicability promise more effective therapeutic strategies.

Язык: Английский

Процитировано

3
Computational methods and key considerations for in silico design of proteolysis targeting chimera (PROTACs) DOI
Amr E. Abbas, Fei Ye

International Journal of Biological Macromolecules, Год журнала: 2024, Номер 277, С. 134293 - 134293

Опубликована: Июль 29, 2024

Язык: Английский

Процитировано

3
PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives DOI Creative Commons
André T. S. Vicente, Jorge A. R. Salvador

MedComm, Год журнала: 2024, Номер 5(6)

Опубликована: Июнь 1, 2024

Abstract Leukemia is a heterogeneous group of life‐threatening malignant disorders the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, long‐term sequelae occur in significant proportion patients severely compromise treatment efficacy. The development novel approaches to improve outcomes therefore an unmet need. Recently, drug discovery strategies, including protein degradation, have shown potential advance field personalized medicine for patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) revolutionary compounds that allow selective degradation by ubiquitin–proteasome Developed against wide range cancer targets, they show promising overcoming many drawbacks associated with conventional therapies. Following exponential growth antileukemic PROTACs, this article reviews PROTAC‐mediated leukemia‐associated targets. Chemical structures, vitro vivo activities, pharmacokinetics, pharmacodynamics, clinical trials PROTACs critically discussed. Furthermore, advantages, challenges, future perspectives covered, order understand these may as drugs treatment.

Язык: Английский

Процитировано

1
MicroRNA‐Triggered Programmable DNA‐Encoded Pre‐PROTACs for Cell‐Selective and Controlled Protein Degradation DOI
Jiayin Zhan, Xiang Li, Zhe Feng

и другие.

Angewandte Chemie International Edition, Год журнала: 2024, Номер unknown

Опубликована: Окт. 9, 2024

Abstract Proteolysis‐targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on‐demand protein degradation. Here, we developed a miR NA‐ i nitiated ssembled pre‐PRO TAC (miRiaTAC) platform that enables the activation termination target degradation in cell type‐specific manner. Using miRNA‐21 as model, engineered DNA hairpins labeled with JQ‐1 pomalidomide facilitated modular assembly DNA‐encoded pre‐PROTACs through hybridization chain reaction. This configuration promoted selective polyubiquitination BRD4 upon miR‐21 initiation, highlighting significant minimal systemic toxicity. Furthermore, incorporates photolabile groups, enabling precise optical control during assembly/disassembly, mitigating risk excessive Additionally, by introducing secondary ligand targeting CDK6, these were used scaffold for programmable active miRiaTACs containing two different warheads exact stoichiometry, orthogonal multitarget The integration near‐infrared light‐mediated photodynamic therapy an upconversion nanosystem further enhanced efficacy potent vivo anticancer activity. We anticipate miRiaTAC represents intersection between dynamic nanotechnology PROTAC, potentially expanding versatility PROTAC toolkit cancer therapy.

Язык: Английский

Процитировано

1
Mitochondria-Targeting Artesunate-Rhein Conjugates: Linker-Modulated Cell-Permeability, Heme-Affinity and Anticancer Activity DOI
Dandan Wang, Li He, Minghui Qi

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 282, С. 117100 - 117100

Опубликована: Ноя. 24, 2024

Язык: Английский

Процитировано

1
MicroRNA‐Triggered Programmable DNA‐Encoded Pre‐PROTACs for Cell‐Selective and Controlled Protein Degradation DOI

Jiayin Zhan,

Xiang Li, Zhe Chuan Feng

и другие.

Angewandte Chemie, Год журнала: 2024, Номер unknown

Опубликована: Окт. 9, 2024

Abstract Proteolysis‐targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on‐demand protein degradation. Here, we developed a miR NA‐ i nitiated ssembled pre‐PRO TAC (miRiaTAC) platform that enables the activation termination target degradation in cell type‐specific manner. Using miRNA‐21 as model, engineered DNA hairpins labeled with JQ‐1 pomalidomide facilitated modular assembly DNA‐encoded pre‐PROTACs through hybridization chain reaction. This configuration promoted selective polyubiquitination BRD4 upon miR‐21 initiation, highlighting significant minimal systemic toxicity. Furthermore, incorporates photolabile groups, enabling precise optical control during assembly/disassembly, mitigating risk excessive Additionally, by introducing secondary ligand targeting CDK6, these were used scaffold for programmable active miRiaTACs containing two different warheads exact stoichiometry, orthogonal multitarget The integration near‐infrared light‐mediated photodynamic therapy an upconversion nanosystem further enhanced efficacy potent vivo anticancer activity. We anticipate miRiaTAC represents intersection between dynamic nanotechnology PROTAC, potentially expanding versatility PROTAC toolkit cancer therapy.

Язык: Английский

Процитировано

0
Precision-engineered PROTACs minimize off-tissue effects in cancer therapy DOI Creative Commons

Jianghua Shi,

Luo Wang,

Xuanwei Zeng

и другие.

Frontiers in Molecular Biosciences, Год журнала: 2024, Номер 11

Опубликована: Ноя. 22, 2024

Proteolysis-targeting chimeras (PROTACs) offer a groundbreaking approach to selectively degrade disease-related proteins by utilizing the ubiquitin-proteasome system. While this strategy shows great potential in preclinical and clinical settings, off-tissue effects remain major challenge, leading toxicity healthy tissues. This review explores recent advancements aimed at improving PROTAC specificity, including tumor-specific ligand-directed PROTACs, pro-PROTACs activated tumor environments, E3 ligase overexpression strategies. Innovations such as PEGylation nanotechnology also play role optimizing efficacy. These developments hold promise for safer, more effective cancer therapies, though challenges translation.

Язык: Английский

Процитировано

0