Reactive oxygen species-responsive Pre-PROTAC for tumor-specific protein degradation

Liu, Haixia; Ren, Chaowei; Sun, Renhong; Zhan, Yuexiong; Yang, Xiaobao; Jiang, Biao; Chen, Hongli

doi:10.1039/d2cc03367d

Cited by 24 publications

(20 citation statements)

References 28 publications

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“…Liu et al. also reported PROTACs activated by ROS 122 (Figure 6C). They constructed ROS‐PROTAC by introducing arylboronic acid into the parental PROTACs and observed that it could be activated by endogenous ROS and effectively degrade the target protein BRD3.…”

Section: Precision Guidance: Regulatory Activation and Targeted Deliverymentioning

confidence: 62%

“…(A) AP‐PROTAC is more active at trans ‐configuration and can be converted to 99% cis‐isomers under 365 nm UV irradiation. Therefore it can be easily regulated; 115 (B) Only by discarding the HALG with the help of hypoxia conditions can the Ha‐PROTAC be activated, or HALG is going to hinder EGFR from being targeted; 116 (C) ROS is able to remove arylboronic acid which blocks E3 ligase from the PROTAC and activate it, therefore induces BRD4 degradation; 122 (D) The regulation of PROTAC can also be regulated by enzyme‐catalyzed activation. With the help of overexpressed NQO1 in cancer cells, Caged‐PROTAC will be released and activated 119 …”

Section: Precision Guidance: Regulatory Activation and Targeted Deliverymentioning

confidence: 99%

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From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

Zhao

Chen

Huang

et al. 2023

Interdisciplinary Medicine

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Proteolysis-targeting chimeras (PROTACs) is a targeted protein degradation (TPD) technique effected by hijacking the ubiquitin-proteasome system (UPS) of the cells. A PROTAC molecule specifically binds to its protein of interest (POI) and recruits an E3 ligase to assemble a ternary complex. The POI was subsequently ubiquitinated, followed by being degraded by proteasomes. After 20 years of development, PROTAC technology has made a significant progress, and quite some candidates have entered clinical trials. Along with the excitement of realizing that PROTAC technology can develop therapeutics toward those traditionally believed "undruggable" targets; there are still unmet demands in PROTAC design, screening, and intracellular availability. PROTAC technology is rapidly advancing from employing traditional medicinal chemistry methodologies to integrating state-of-the-art chemical biology technologies, becoming a typical example of interdisciplinary medicine. This review summarizes the progress made in PROTAC technology in recent years, including expanding new targets, developing dual-target PROTACs, rational design and screening strategies, regulatory activation, targeted delivery, and developing biological macromolecule-contained PROTACs.

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Section: Precision Guidance: Regulatory Activation and Targeted Deliverymentioning

confidence: 62%

Section: Precision Guidance: Regulatory Activation and Targeted Deliverymentioning

confidence: 99%

From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

Zhao

Chen

Huang

et al. 2023

Interdisciplinary Medicine

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show abstract

“…In contrast, although glutarimide nitrogen of the CRBN binder can serve as a chemical handle in some cases, unexpected problems may occur due to incomplete cleavage and poor stability. 35,53 Indeed, there are still many other MOAs that can be employed for the development of tumor-targeting PROTACs. Using similar strategies, it is possible to develop pro-PROTACs for treating diseases other than cancer.…”

Section: Discussionmentioning

confidence: 99%

“…52 Liu et al developed a class of ROS-responsive PROTACs recruiting CRBN E3 ligase for selective degradation of BRD3. 53 Prodrug 32 (Figure 7B) was obtained by installing aryl boronic acid on the aromatic amine group of the lenalidomide fragment. When treated with H 2 O 2 , aryl boronic acid-caged pro-PROTAC 32 was converted to a phenolderived intermediate and underwent subsequent 1,6-benzyl elimination to release the active PROTAC.…”

Section: Pro-protacs Activated By Other Moasmentioning

confidence: 99%

Recent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity

et al. 2023

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Proteolysis-targeting chimera (PROTAC) technology represents a novel and promising modality for targeted protein degradation with transformative implications for the clinical management of various diseases. Despite notable advantages, the possibility of on-target off-tumor toxicity in healthy cells represents a critical challenge to clinical applications in cancer treatment. Researchers are currently exploring strategies to enhance targeted degradation activity in a cell-selective manner to minimize undesirable side effects. In this Perspective, we highlight innovative approaches for prodrug-based PROTACs (pro-PROTACs) that facilitate tumor-targeted release. The development of such approaches may further expand the range of potential applications of PROTAC technology within drug development.

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“…Low ROS levels are maintained in normal cells, while it is much higher in the tumor microenvironment [ 32 ]. Chen et al (2022) designed ROS-responsive Pre-PROTACs 3 by conjugating an ROS-triggered leaving group, arylboronic acid, to the parent PROTACs [ 33 ]. This PROTAC molecule 3 was designed by recruiting a CRBN ligand and BRD3 protein ligand to opposite ends connected by varying linkers ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

Emerging Strategies in Proteolysis-Targeting Chimeras (PROTACs): Highlights from 2022

Tamatam

Shin

2023

IJMS

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Targeted protein degradation (TPD) is a promising therapeutic modality that has garnered attention in academic, industrial, and pharmaceutical research for treating diseases such as cancer, neurodegenerative disorders, inflammation, and viral infections. In this context, proteolysis-targeting chimeras (PROTACs) present a reliable technology for degrading disease-causing proteins. PROTACs complement small-molecule inhibitors, which primarily rely on direct protein regulation. From concept-to-clinic, PROTACs have evolved from cell impermeable peptide molecules to orally bioavailable drugs. Despite their potential in medicinal chemistry, certain aspects regarding PROTACs remain unclear. The clinical significance of PROTACs is primarily limited owing to their lack of selectivity and drug-like properties. This review focused on recently reported PROTAC strategies, particularly in 2022. It aimed to address and overcome the challenges posed by classical PROTACs by correlating them with emerging approaches with improved selectivity and controllability, cell permeability, linker flexibility, druggability, and PROTAC-based approaches, developed in 2022. Furthermore, recently reported PROTAC-based approaches are discussed, highlighting each of their advantages and limitations. We predict that several improved PROTAC molecules will be accessible for treating patients exhibiting various conditions, including cancer, neurodegenerative disorders, inflammation, and viral infections.

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Reactive oxygen species-responsive Pre-PROTAC for tumor-specific protein degradation

Abstract: By introducing a Reactive oxygen species (ROS) triggered leaving group (arylboronic acid) to the parent PROTACs. ROS-responsive Pre-PROTACs were designed and evaluated. Pre-PROTAC (7) efficiently degrade the target proteins BRD3...

Cited by 24 publications

References 28 publications

From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

Recent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity

Emerging Strategies in Proteolysis-Targeting Chimeras (PROTACs): Highlights from 2022

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