Chemistries of bifunctional PROTAC degraders

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(16), P. 7066 - 7114

Published: Jan. 1, 2022

Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins.

Language: Английский

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Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 145(1), P. 385 - 391

Published: Dec. 21, 2022

Proteolysis targeting chimera (PROTAC) is an emerging protein degradation strategy, which shows excellent advantages in those so-called "undruggable" proteins. However, the potential systemic toxicity of PROTACs caused by undesired off-tissue may limit application clinical practice. Here we reported a radiotherapy-triggered PROTAC prodrug (RT-PROTAC) activation strategy to precisely and spatiotemporally control through X-ray radiation. We demonstrated this concept incorporating inducible phenyl azide-cage bromodomain (BRD)-targeting form first RT-PROTAC. The RT-PROTAC exhibits little activity but can be activated radiation vitro vivo. Activated degrades BRD4 BRD2 with comparable effect degrader synergistic antitumor potency radiotherapy MCF-7 xenograft model. Our work provides alternative vivo points avenue for reducing PROTACs.

Language: Английский

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Trends in Molecular Properties, Bioavailability, and Permeability across the Bayer Compound Collection

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(4), P. 2347 - 2360

Published: Feb. 8, 2023

For oral drugs, medicinal chemists aim to design compounds with high bioavailability, of which permeability is a key determinant. Taking advantage >2000 tested in rat bioavailability studies and >20,000 Caco2 assays at Bayer, we have examined the molecular properties governing permeability. In addition classical parameters such as logD weight, also investigated relationship between calculated pKa We find that neutral retain up weight limit 700, while stronger acids bases are restricted weights 400–500. investigate trends for common hydrogen bond donors acceptors, polar surface area, aromatic ring count, rotatable bonds, including exceed Lipinski’s rule five (Ro5). These property–structure relationships combined provide guidelines bioavailable drugs both traditional “beyond 5” (bRo5) chemical space.

Language: Английский

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Aptamer-Based Targeted Protein Degradation

ACS Nano, Journal Year: 2023, Volume and Issue: 17(7), P. 6150 - 6164

Published: March 21, 2023

The selective removal of misfolded, aggregated, or aberrantly overexpressed protein plays an essential role in maintaining protein-dominated biological processes. In parallel, the precise knockout abnormal proteins is inseparable from accurate identification within complex environments. Guided by these precepts, small molecules, antibodies, are commonly used as recognition tools for developing targeted degradation (TPD) technology. Indeed, TPD has shown tremendous prospects chronic diseases, rare cancer research, and other fields. Meanwhile, aptamers short RNA DNA oligonucleotides that can bind to target with high specificity strong affinity. Accordingly, actively designing constructing this perspective, we provide a brief introduction technology its current progress, summarize application challenges. Recent advances aptamer-based reviewed, together corresponding challenges outlooks.

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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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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Characteristic roadmap of linker governs the rational design of PROTACs

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4266 - 4295

Published: April 11, 2024

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected linker. The linker plays pivotal role determining PROTAC's biodegradative efficacy. Advanced and rationally designed linkers are under development. Nonetheless, correlation between characteristics efficacy remains under-investigated. Consequently, this study will present multidisciplinary analysis of their impact on efficacy, thereby guiding rational design linkers. We primarily discuss structural types linkers, optimization strategies used design. Furthermore, we how factors like length, group type, flexibility, linkage site affect biodegradation efficiency PROTACs. believe that work contribute towards advancement research area.

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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PROTACs: Current and Future Potential as a Precision Medicine Strategy to Combat Cancer

Molecular Cancer Therapeutics, Journal Year: 2024, Volume and Issue: 23(4), P. 454 - 463

Published: Jan. 10, 2024

Abstract Proteolysis targeting chimeras (PROTAC) are an emerging precision medicine strategy, which targets key proteins for proteolytic degradation to ultimately induce cancer cell killing. These hetero-bifunctional molecules hijack the ubiquitin proteasome system selectively add polyubiquitin chains onto a specific protein target degradation. Importantly, PROTACs have capacity virtually any intracellular and transmembrane degradation, including oncoproteins previously considered undruggable, strategically positions at crossroads of multiple research areas. In this review, we present normal functions regulation describe application improve efficacy current broad-spectrum therapeutics. We subsequently potential exploit vulnerabilities through synthetic genetic approaches, may expedite development, translation, utility novel therapies in cancer. Finally, challenges associated with ongoing efforts overcome these issues streamline clinical translation. Ultimately, lead their routine use, is expected revolutionize treatment strategies, delay familial onset, lives outcomes those living

Language: Английский

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BRD4-targeted photodegradation nanoplatform for light activatable melanoma therapy

Biomaterials, Journal Year: 2025, Volume and Issue: 317, P. 123101 - 123101

Published: Jan. 10, 2025

Language: Английский

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