Tracking the PROTAC degradation pathway in living cells highlights the importance of ternary complex measurement for PROTAC optimization

Cell chemical biology, Journal Year: 2023, Volume and Issue: 30(7), P. 753 - 765.e8

Published: June 25, 2023

Language: Английский

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Self-Assembled Nano-PROTAC Enables Near-Infrared Photodynamic Proteolysis for Cancer Therapy

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(30), P. 16642 - 16649

Published: July 21, 2023

Confining the protein degradation activity of proteolysis-targeting chimera (PROTAC) to cancer lesions ensures precision treatment. However, it still remains challenging precisely control PROTAC function in tumor regions vivo. We herein describe a near-infrared (NIR) photoactivatable nano-PROTAC (NAP) for remote-controllable proteolysis tumor-bearing mice. NAP is formed by molecular self-assembly from an amphiphilic conjugate linked with NIR photosensitizer through singlet oxygen (1O2)-cleavable linker. The initially silenced but can be remotely switched on upon photoirradiation generate 1O2 photosensitizer. demonstrated that enabled tumor-specific bromodomain-containing 4 (BRD4) light-instructed manner. This combination photodynamic therapy (PDT) elicited effective suppression growth. work thus presents novel approach spatiotemporal over targeted PROTAC.

Language: Английский

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Small molecule approaches to targeting RNA

Nature Reviews Chemistry, Journal Year: 2024, Volume and Issue: 8(2), P. 120 - 135

Published: Jan. 26, 2024

Language: Английский

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New-generation advanced PROTACs as potential therapeutic agents in cancer therapy

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 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.

Language: Английский

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PROTAC Prodrug‐Integrated Nanosensitizer for Potentiating Radiation Therapy of Cancer

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(23)

Published: Feb. 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.

Language: Английский

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Discovery of a PROTAC degrader for METTL3-METTL14 complex

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(1), P. 177 - 183.e17

Published: Jan. 1, 2024

Language: Английский

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Nano-PROTACs: state of the art and perspectives

Nanoscale, Journal Year: 2024, Volume and Issue: 16(9), P. 4378 - 4391

Published: Jan. 1, 2024

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

Language: Английский

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Cell Membrane as A Promising Therapeutic Target: From Materials Design to Biomedical Applications

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(18)

Published: Feb. 19, 2024

The cell membrane is a crucial component of cells, protecting their integrity and stability while facilitating signal transduction information exchange. Therefore, disrupting its structure or impairing functions can potentially cause irreversible damage. Presently, the tumor recognized as promising therapeutic target for various treatment methods. Given extensive research focused on membranes, it both necessary timely to discuss these developments, from materials design specific biomedical applications. This review covers treatments based functional targeting membrane, ranging well-known membrane-anchoring photodynamic therapy recent lysosome-targeting chimaeras protein degradation. diverse mechanisms are introduced in following sections: phototherapy, self-assembly situ biosynthesis degradation proteins by chimeras. In each section, we outline conceptual general derived numerous studies, emphasizing representative examples understand advancements draw inspiration. Finally, some challenges future directions membrane-targeted our perspective. aims engage multidisciplinary readers encourage researchers related fields advance fundamental theories practical applications membrane-targeting agents.

Language: Английский

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

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 276, P. 116725 - 116725

Published: July 30, 2024

Language: Английский

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Expanding the horizons of targeted protein degradation: A non-small molecule perspective

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(6), P. 2402 - 2427

Published: Jan. 21, 2024

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel

Language: Английский

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