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

New-generation advanced PROTACs as potential therapeutic agents in cancer therapy DOI Creative Commons
Chao Wang, Yujing Zhang,

Wujun Chen

и другие.

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Май 21, 2024

Abstract Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit endogenous E3 ubiquitin ligases facilitate degradation of interest (POIs) through ubiquitin–proteasome system (UPS) in cyclic catalytic manner. Despite recent endeavors advance utilization clinical settings, majority fail progress beyond preclinical phase drug development. There are multiple factors impeding market entry PROTACs, insufficiently precise favorable POIs standing out as one most formidable obstacles. Recently, there been exploration new-generation advanced including PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, improve vivo efficacy PROTACs. These improved possess capability mitigate undesirable physicochemical characteristics inherent thereby enhancing their targetability reducing off-target side effects. The will mark pivotal turning point realm targeted protein degradation. In this comprehensive review, we meticulously summarized state-of-the-art advancements achieved by these cutting-edge elucidated underlying design principles, deliberated upon prevailing encountered, provided an insightful outlook on future prospects within field.

Язык: Английский

Процитировано

35
PROTAC Prodrug‐Integrated Nanosensitizer for Potentiating Radiation Therapy of Cancer DOI
Shunan Zhang, Yi Lai,

Jiaxing Pan

и другие.

Advanced Materials, Год журнала: 2024, Номер 36(23)

Опубликована: Фев. 14, 2024

Abstract Radiation therapy (RT) is one of the primary options for clinical cancer therapy, in particular advanced head and neck squamous cell carcinoma (HNSCC). Herein, crucial role bromodomain‐containing protein 4 (BRD4)‐RAD51 associated 1 (RAD51AP1) axis sensitizing RT HNSCC revealed. A versatile nanosensitizer (RPB7H) thus innovatively engineered by integrating a PROteolysis TArgeting Chimeras (PROTAC) prodrug (BPA771) hafnium dioxide (HfO 2 ) nanoparticles to downregulate BRD4‐RAD51AP1 pathway sensitize tumor RT. Upon intravenous administration, RPB7H selectively accumulate at tissue internalize into cells recognizing neuropilin‐1 overexpressed mass. HfO enhance effectiveness amplifying X‐ray deposition, intensifying DNA damage, boosting oxidative stress. Meanwhile, BPA771 can be activated RT‐induced H O secretion degrade BRD4 inactivate RAD51AP1, impeding damage repair. This nanosensitizer, combined with irradiation, effectively regresses growth mouse model. The findings introduce PROTAC prodrug‐based radiosensitization strategy targeting axis, may offer promising avenue augment more effective therapy.

Язык: Английский

Процитировано

30
Nano-PROTACs: state of the art and perspectives DOI
Jie Zhong, Ruiqi Zhao, Yuji Wang

и другие.

Nanoscale, Год журнала: 2024, Номер 16(9), С. 4378 - 4391

Опубликована: Янв. 1, 2024

Schematic illustration of the combinational strategy nanotechnology and PROTACs (Nano-PROTACs): typical shortcomings traditional nanotechnology-based strategies for PROTAC drugs optimization.

Язык: Английский

Процитировано

23
Selective Protein of Interest Degradation through the Split-and-Mix Liposome Proteolysis Targeting Chimera Approach DOI

Chunli Song,

Zijun Jiao,

Zhanfeng Hou

и другие.

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(40), С. 21860 - 21870

Опубликована: Сен. 14, 2023

Proteolysis Targeting Chimera (PROTAC) technology represents a promising new approach for target protein degradation using cellular ubiquitin-proteasome system. Recently, we developed split-and-mix nanoplatform based on peptide self-assembly, which could serve as self-adjustable platform multifunctional applications. However, the lower drug efficacy limits further biomedical applications of peptide-based SM-PROTAC. In this study, develop novel PROTAC system liposome self-assembly (LipoSM-PROTAC), concurrent with modification FA (folate) to enhance its tumor-targeting capabilities. Estrogen receptors (ERα) were chosen interest (POI) validate Lipo degraders. Results demonstrate that can be efficiently and selectively taken up into cells by receptor-positive (FR+) degrade POI significantly reduced concentration. Compared SM-PROTACs, our designed LipoSM-PROTAC achieve therapeutic concentration provide opportunities clinical translational potential. Overall, LipoSM-based shows higher efficacy, offers potential other biomolecule regulations.

Язык: Английский

Процитировано

27
Light‐Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy DOI Creative Commons
Jiwoong Choi,

Byeongmin Park,

Jung Yeon Park

и другие.

Advanced Materials, Год журнала: 2024, Номер 36(38)

Опубликована: Июнь 20, 2024

Abstract While proteolysis‐targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment via targeted protein degradation, precisely activating them in tissues and preventing uncontrolled proteolysis at off‐target sites remain challenging. Herein, a light‐triggered PROTAC nanoassembly (LPN) photodynamic indoleamine 2,3‐dioxygenase (IDO) is reported. The LPN derived from self‐assembly of prodrug conjugates, which comprise PROTAC, cathepsin B‐specific cleavable peptide linker, photosensitizer, without any additional carrier materials. In colon models, intravenously injected LPNs initially silence activity PROTACs accumulate significantly due to an enhanced permeability retention effect. Subsequently, cancer biomarker B begins trigger release active through enzymatic cleavage linkers. Upon light irradiation, cells undergo immunogenic cell death induced by therapy promote activation effector T cells, while continuous IDO degradation simultaneously blocks tryptophan metabolite‐regulated regulatory‐T‐cell‐mediated immunosuppression. Such LPN‐mediated combinatorial effectively inhibits growth, metastasis, recurrence. Collectively, this study presents promising nanomedicine, designed synergize with other immunotherapeutic modalities, more effective safer immunotherapy.

Язык: Английский

Процитировано

17
Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy DOI

Zhifeng Zou,

Lei Yang,

Hui-Jun Nie

и другие.

Acta Pharmacologica Sinica, Год журнала: 2024, Номер 45(8), С. 1740 - 1751

Опубликована: Апрель 12, 2024

Язык: Английский

Процитировано

16
PROTAC-biomacromolecule conjugates for precise protein degradation in cancer therapy: A review DOI
Chao Wang, Yujing Zhang, Wanpeng Yu

и другие.

International Journal of Biological Macromolecules, Год журнала: 2024, Номер 261, С. 129864 - 129864

Опубликована: Янв. 30, 2024

Язык: Английский

Процитировано

11
Self‐Oxygenating PROTAC Microneedle for Spatiotemporally‐Confined Protein Degradation and Enhanced Glioblastoma Therapy DOI Open Access
Xingyu Jiang, Yi Lai,

Wenzheng Xia

и другие.

Advanced Materials, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Abstract Glioblastoma (GBM) is the most aggressive subtype of primary brain tumors, which marginally respond to standard chemotherapy due blood‐brain barrier (BBB) and low tumor specificity therapeutics. Herein, a double‐layered microneedle (MN) patch rationally engineered by integrating acid light dual‐activatable PROteolysis TArgeting Chimera (PROTAC) nanoparticles self‐oxygenating BSA‐MnO 2 (BM) for GBM treatment. The MN administrated at site locally deliver PROTAC prodrug BM nanoparticles. are rapidly released from outer layer specifically activated in acidic intracellular environment cells. Subsequently, near‐infrared activates photosensitizer produce singlet oxygen ( 1 O ) through photodynamic therapy (PDT), thereby triggering spatiotemporally‐tunable degradation bromodomain extraterminal protein 4 (BRD4). nanoparticles, inner MN, serve as an supply station, counteracts hypoxia converting hydrogen peroxide (H into (O ), thus promoting PDT activation. This prodrug‐integrated significantly inhibits growth both subcutaneous orthotopic models. study describes first strategy highly efficient therapy, potentially advancing precise other kinds refractory tumors.

Язык: Английский

Процитировано

2
High‐Throughput Miniaturized Synthesis of PROTAC‐Like Molecules DOI
Ye Tian, Maximilian Seifermann,

Liana Bauer

и другие.

Small, Год журнала: 2024, Номер 20(26)

Опубликована: Янв. 22, 2024

The development of miniaturized high-throughput in situ screening platforms capable handling the entire process drug synthesis to final is essential for advancing discovery future. In this study, an approach based on combinatorial solid-phase synthesis, enabling efficient libraries proteolysis targeting chimeras (PROTACs) array format presented. This on-chip platform allows direct biological without need transfer steps. UV-induced release target molecules into individual droplets facilitates further experimentation. Utilizing a mitogen-activated protein kinase kinases (MEK1/2) degrader as template, series 132 novel PROTAC-like synthesized using Ugi reaction. These compounds are characterized various methods, including matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) imaging, while consuming only few milligrams starting materials total. Furthermore, feasibility culturing cancer cells modified spots and quantifying effect MEK suppression demonstrated. lays foundation potent PROTACs potential anticancer activity offers accelerating by integrating steps same array.

Язык: Английский

Процитировано

6
Ultrasound Controllable Release of Proteolysis Targeting Chimeras for Triple Negative Breast Cancer Treatment DOI Creative Commons

Hongye He,

Feng Li,

Rui Tang

и другие.

Biomaterials Research, Год журнала: 2024, Номер 2024

Опубликована: Июль 10, 2024

Triple-negative breast cancer (TNBC) is a special subtype of cancer, which highly aggressive and incurable. Here, we proposed an ultrasound activatable bromodomain-containing protein 4 (BRD4) proteolysis targeting chimera (PROTAC) release strategy for the first time precisely controlled degradation in preclinical TNBC model. Through combination PROTAC ultrasound-targeted microbubble destruction (UTMD) technology, present also aims to concurrently solve major limitations poor loading capacity microbubbles undesirable membrane permeability PROTAC. (ARV-825)-encapsulated microbubbles, ARV-MBs, were developed efficacious treatment vitro vivo. The synthesized showed ultrasound-responsive drug ability, could effectively promote penetration into tumor site cell. Under ultrasound, ARV-MBs play effective antitumor effect by potentiating ubiquitination BRD4 tumor. current study may provide new idea promoting clinical translation drug-loaded PROTAC, offer therapeutic modality TNBC.

Язык: Английский

Процитировано

4