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

Molecular Cancer Therapeutics, Год журнала: 2024, Номер 23(4), С. 454 - 463

Опубликована: Янв. 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

Язык: Английский

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Targeted protein degradation in cancers: Orthodox PROTACs and beyond

The Innovation, Год журнала: 2023, Номер 4(3), С. 100413 - 100413

Опубликована: Март 15, 2023

Targeted protein degradation (TPD) is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors. Proteolysis-targeting chimera (PROTAC) technology can be used target proteins by hijacking ubiquitin-proteasome system. Conceptually, PROTAC aims "undruggable" majority in human proteome. Through constant exploration and optimization PROTACs exploitation other TPD strategies over two decades, has expanded from theoretical studies clinical strategies, with practical applications oncological, immunological, diseases. In this review, we introduce mechanisms, features, molecular targets orthodox summarize drugs under study cancer therapeutics trials. We also discuss derivatives such lysosome-targeting chimeras, autophagy-targeting glue strategies. Collectively, summarized herein support full potential biomedical industry.

Язык: Английский

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Current advances and development strategies of orally bioavailable PROTACs

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 261, С. 115793 - 115793

Опубликована: Сен. 7, 2023

Язык: Английский

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

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

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Proteolysis-Targeting Chimera (PROTAC) Delivery into the Brain across the Blood-Brain Barrier

Antibodies, Год журнала: 2023, Номер 12(3), С. 43 - 43

Опубликована: Июнь 26, 2023

Drug development for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s and Huntington’s disease has challenging difficulties due to the pharmacokinetic impermeability based on blood-brain barrier (BBB) well blurriness of pharmacodynamic targets their unclarified pathogenesis complicated progression mechanisms. Thus, in order produce innovative central nervous system (CNS) agents patients suffering from CNS diseases, effective, selective delivery into brain across BBB should be developed. Currently, proteolysis-targeting chimeras (PROTACs) attract rising attention a new modality degrade arbitrary intracellular proteins by ubiquitin-proteasome system. The internalizations peptide-based PROTACs cell-penetrating peptides that small molecule-based through passive diffusion lack cell selectivity. Therefore, these approaches may bring off-target side effects wrong distribution. Furthermore, efflux transporters multiple drug resistance 1 (MDR1) expressed at might interrupt entry brain. Nonetheless, intelligent using machinery systems absorb nutrition homeostasis, carrier-mediated transport (CMT) or receptor-mediated transcytosis (RMT), can established. with N-containing groups are recognized proton-coupled organic cation antiporter cross CMT. PROTAC-antibody conjugates (PACs) RMT. Subsequently, released interstitial fluid would transported cells neurons then demonstrate protein degradation. In this review, I introduce potential advantages PROTAC CMT RMT PACs non-invasive way.

Язык: Английский

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Proteomic approaches advancing targeted protein degradation

Trends in Pharmacological Sciences, Год журнала: 2023, Номер 44(11), С. 786 - 801

Опубликована: Сен. 29, 2023

Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) molecular glue (MG) degraders (MGDs) represent the most advanced approaches, with some already used in clinical settings. Despite these advances, still faces many challenges, pertaining to both development of effective, selective, tissue-penetrant understanding their mode action. In this review, we focus on progress made addressing challenges. particular, discuss utility application recent proteomic as indispensable tools enable insights into degrader development, including target engagement, selectivity, efficacy, safety,

Язык: Английский

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Inhibitors to degraders: Changing paradigm in drug discovery

iScience, Год журнала: 2024, Номер 27(5), С. 109574 - 109574

Опубликована: Март 26, 2024

The chemical understanding of biological processes provides not only a deeper insight but also solution to abnormal functioning. Protein degradation, natural process for debris removal in the cell, has been studied years. recent finding that degradation pathways can be utilized therapeutic purposes is paradigm shift drug discovery approach. Methods such as Proteolysis Targeting Chimera (PROTAC), lysosomal targeting chimera, hydrophobic tagging, AUtophagy TArgeting Chimera, AUTOphagy and several other variants these methods have made considerable impact on way design. Few selected examples testify huge wave change way. design based targeted protein powerful tool our arsenal. More molecules will invented uncover hidden secrets functioning provide enduring solutions unmet medical needs.

Язык: Английский

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TACkling Cancer by Targeting Selective Protein Degradation

Pharmaceutics, Год журнала: 2023, Номер 15(10), С. 2442 - 2442

Опубликована: Окт. 10, 2023

Targeted protein degradation has emerged as an alternative therapy against cancer, offering several advantages over traditional inhibitors. The new degrader drugs provide different therapeutic strategies: they could cross the phospholipid bilayer membrane by addition of specific moieties to extracellular proteins. On other hand, efficiently improve process generation a ternary complex structure E3 ligase. Herein, we review current trends in use TAC-based technologies (TACnologies), such PROteolysis TArgeting Chimeras (PROTAC), PHOtochemically (PHOTAC), CLIck-formed Proteolysis (CLIPTAC), AUtophagy (AUTAC), AuTophagosome TEthering Compounds (ATTEC), LYsosome-TArgeting (LYTAC), and DeUBiquitinase (DUBTAC), experimental development their progress towards clinical applications.

Язык: Английский

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Nano-Proteolysis Targeting Chimeras (Nano-PROTACs) in Cancer Therapy

International Journal of Nanomedicine, Год журнала: 2024, Номер Volume 19, С. 5739 - 5761

Опубликована: Июнь 1, 2024

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have the capability to induce specific protein degradation. While playing a revolutionary role in effectively degrading of interest (POI), PROTACs encounter certain limitations impede their clinical translation. These encompass off-target effects, inadequate cell membrane permeability, and hook effect. The advent nanotechnology presents promising avenue surmount challenges associated with conventional PROTACs. utilization nano-proteolysis targeting (nano-PROTACs) holds potential enhance tissue accumulation, augment enable controlled release. Consequently, this approach has capacity significantly controllable degradation target proteins. Additionally, they synergistic effect by combining other therapeutic strategies. This review comprehensively summarizes structural basis, advantages, Furthermore, it highlights latest advancements nanosystems engineered for delivering PROTACs, as well development nano-sized employing nanocarriers linkers. Moreover, delves into underlying principles tailored specifically alongside current prospects research. In conclusion, integration harbors vast enhancing anti-tumor treatment response expediting

Язык: Английский

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CRBN‐PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications

Chemical Biology & Drug Design, Год журнала: 2024, Номер 104(5)

Опубликована: Ноя. 1, 2024

Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as therapeutic target in cancer. CRBN regulates degradation various proteins cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are novel approach that uses cell's system to remove disease-causing selectively. CRBN-dependent work by tagging harmful for destruction through ubiquitin-proteasome system. This strategy offers several advantages over traditional protein inhibition methods, potential overcome drug resistance. Recent progress developing CRBN-based shown promising preclinical results both hematologic malignancies solid tumors. Additionally, have enhanced our understanding CRBN's role cancer, potentially serving biomarkers patient stratification predicting responses. In this review, we delineate mechanisms action (CRBN-PROTACs), summarize recent advances clinical applications, provide perspective on future development.

Язык: Английский

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