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

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

Опубликована: Июль 30, 2024

Язык: Английский

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Drugtamer‐PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy

Advanced Science, Год журнала: 2024, Номер 11(25)

Опубликована: Апрель 19, 2024

Abstract Proteolysis‐targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. To overcome the inherent limitations of conventional PROTACs, an innovative drugtamer‐PROTAC conjugation approach is developed to enhance tumor targeting antitumor potency. Specifically, smart prodrug designed by conjugating “drugtamer” nicotinamide phosphoribosyltransferase (NAMPT) PROTAC using microenvironment responsible linker. The consists fluorouridine nucleotide DNA‐like oligomer. Compared NAMPT combination + fluorouracil, AS‐2F‐NP demonstrates superior targeting, efficient cellular uptake, improved in vivo potency reduced side effects. This study provides precise delivery synergistic agents.

Язык: Английский

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Nanomaterials Enhanced Sonodynamic Therapy for Multiple Tumor Treatment

Nano-Micro Letters, Год журнала: 2025, Номер 17(1)

Опубликована: Фев. 24, 2025

Abstract Sonodynamic therapy (SDT) as an emerging modality for malignant tumors mainly involves in sonosensitizers and low-intensity ultrasound (US), which can safely penetrate the tissue without significant attenuation. SDT not only has advantages including high precision, non-invasiveness, minimal side effects, but also overcomes limitation of low penetration light to deep tumors. The cytotoxic reactive oxygen species be produced by utilization combined with US kill tumor cells. However, underlying mechanism been elucidated, its unsatisfactory efficiency retards further clinical application. Herein, we shed on main mechanisms types sonosensitizers, organic inorganic sonosensitizers. Due development nanotechnology, many novel nanoplatforms are utilized this arisen field solve barriers enable continuous innovation. This review highlights potential nanosonosensitizers focus enhanced based monotherapy or synergistic that difficult reach traditional treatment, especially orthotopic cancers.

Язык: Английский

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Cleavage of Homonuclear Chalcogen‐Chalcogen Bonds in a Hybrid Platform in Response to X‐Ray Radiation Potentiates Tumor Radiochemotherapy

Angewandte Chemie International Edition, Год журнала: 2024, Номер 64(1)

Опубликована: Авг. 23, 2024

Chalcogens are used as sensitive redox-responsive reagents in tumor therapy. However, chalcogen bonds triggered by external ionizing radiation, rather than internal environmental stimuli, enable site-directed and real-time drug degradation target lesions. This approach helps to bypass chemoresistance global systemic toxicity, presenting a significant advancement over traditional chemoradiotherapy. In this study, we fabricated hybrid monodisperse organosilica nanoprodrug based on homonuclear single (disulfide (S-S, approximately 240 kJ/mol), diselenium (Se-Se, 172 tellurium (Te-Te, 126 kJ/mol)), including ditelluride-bond-bridged MONs (DTeMSNs), diselenide-bond-bridged (DSeMSNs) disulfide-bond-bridged (DSMSNs). The results demonstrated that differences electronegativities atomic radii influenced their oxidation sensitivities reactivities. Tellurium, with the lowest electronegativity, showed highest sensitivity, followed selenium sulfur. DTeMSNs exhibited highly responsive cleavage upon exposure X-rays, resulting TeO

Язык: Английский

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Strategies for Precise Modulation of Protein Degradation

Accounts of Chemical Research, Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

ConspectusTargeted protein degradation (TPD) technologies, exemplified by proteolysis-targeting chimeras (PROTACs), have revolutionized therapeutic strategies facilitating the selective of pathogenic proteins instead simply inhibiting their functions. This degradation-based strategy offers significant advantages over traditional small-molecule inhibitors, which often block activity without eliminating target. PROTACs function leveraging ubiquitin-proteasome system to selectively degrade target proteins, thus enabling modulation a broader range disease-causing including those that were previously considered undruggable. As result, PROTAC-based therapies gained considerable attention in drug discovery, especially oncology, immunology, and neurodegenerative diseases. However, clinical translation conventional remains challenging due issues such as limited specificity, poor solubility, inadequate cellular permeability, unfavorable pharmacokinetic profiles, absence spatiotemporal resolution.To address these hurdles, various innovative been developed enhance precision degradation. These approaches focus on improving targeted delivery, membrane control with goal overcoming inherent limitations PROTAC designs. For instance, aptamer-conjugated shown great promise tumor selectivity reducing off-target effects through tumor-specific receptor recognition subsequent internalization. Moreover, development drugtamer-PROTAC conjugates enables more precise codelivery agents, optimizing synergistic both modalities while minimizing systemic toxicity. Additionally, RGD peptide-based conjugation capitalize use tumor-homing peptides uptake, improve penetration, increase specificity cells, further toxicities healthy tissues.Another critical advancement is photocontrolled PROTACs, allow for temporal regulation vivo. By light-responsive molecules, systems provide ability trigger at specific time points, offering unparalleled interventions. Furthermore, theranostic combine diagnostic functions, facilitate real-time monitoring events living cells animal models, simultaneous assessment efficacy biomarker visualization.This Account reviews recent advancements design smart highlighting control. innovations promising solutions paving way progress discovery evolution medicine. While discussed present opportunities, we also explore challenges, limitations, future directions translation, insights into potential degrader-based setting.

Язык: Английский

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Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions

Bioconjugate Chemistry, Год журнала: 2024, Номер 35(8), С. 1089 - 1115

Опубликована: Июль 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.

Язык: Английский

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Cleavage of Homonuclear Chalcogen‐Chalcogen Bonds in a Hybrid Platform in Response to X‐Ray Radiation Potentiates Tumor Radiochemotherapy

Angewandte Chemie, Год журнала: 2024, Номер 137(1)

Опубликована: Авг. 23, 2024

Abstract Chalcogens are used as sensitive redox‐responsive reagents in tumor therapy. However, chalcogen bonds triggered by external ionizing radiation, rather than internal environmental stimuli, enable site‐directed and real‐time drug degradation target lesions. This approach helps to bypass chemoresistance global systemic toxicity, presenting a significant advancement over traditional chemoradiotherapy. In this study, we fabricated hybrid monodisperse organosilica nanoprodrug based on homonuclear single (disulfide (S−S, approximately 240 kJ/mol), diselenium (Se−Se, 172 tellurium (Te−Te, 126 kJ/mol)), including ditelluride‐bond‐bridged MONs (DTeMSNs), diselenide‐bond‐bridged (DSeMSNs) disulfide‐bond‐bridged (DSMSNs). The results demonstrated that differences electronegativities atomic radii influenced their oxidation sensitivities reactivities. Tellurium, with the lowest electronegativity, showed highest sensitivity, followed selenium sulfur. DTeMSNs exhibited highly responsive cleavage upon exposure X‐rays, resulting TeO 3 2− . Furthermore, chalcogen‐hybridized was loaded manganese ions (Mn 2+ ) enhance release of Mn during radiotherapy, thereby activating stimulator interferon genes (STING) pathway enhancing immune response inhibit growth. investigation deepens our understanding chalcogens characteristics radiotherapy enriches design principles for nanomedicine prodrugs.

Язык: Английский

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Powering up targeted protein degradation through active and passive tumour-targeting strategies: Current and future scopes

Pharmacology & Therapeutics, Год журнала: 2024, Номер 263, С. 108725 - 108725

Опубликована: Сен. 24, 2024

Язык: Английский

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Prussian blue nanoparticle-based pH-responsive self-assembly for enhanced photothermal and chemotherapy of tumors

Journal of Photochemistry and Photobiology B Biology, Год журнала: 2024, Номер 256, С. 112938 - 112938

Опубликована: Май 10, 2024

Язык: Английский

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Precise Modulation of Protein Degradation by Smart PROTACs

ChemBioChem, Год журнала: 2024, Номер 26(1)

Опубликована: Окт. 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.

Язык: Английский

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