Targeted protein degradation: mechanisms, strategies and application

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Апрель 4, 2022

Abstract Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application activity modulators, particularly inhibitors, has been the mainstream in development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology emerged as one most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. addition PROTAC, many different targeted degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), Antibody-based PROTAC (AbTAC), are emerging. These technologies have only greatly expanded scope TPD, also provided fresh insights into discovery. Here, we summarize advances major TPD technologies, discuss their potential applications, hope provide a prime for both biologists chemists who interested this vibrant field.

Язык: Английский

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Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 13, 2023

Abstract Targeted protein degradation via “hijacking” of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design PROTACs is challenging; multiple steps involved in PROTAC-induced make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and by employing von Hippel–Lindau (VHL) recruiting for two different target proteins, SMARCA2 BRD4. Ternary-complex attributes activity parameters are evaluated varying components PROTAC’s architecture. Ternary binding affinity cooperativity correlates well with potency initial rates degradation. Additionally, develop ternary-complex structure modeling workflow calculate total buried surface area at interface, which agreement measured affinity. Our findings predictive framework guide potent degraders.

Язык: Английский

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

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

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

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(6), С. 2402 - 2427

Опубликована: Янв. 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

Язык: Английский

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Formation of C(sp²)–C(sp³) Bonds Instead of Amide C–N Bonds from Carboxylic Acid and Amine Substrate Pools by Decarbonylative Cross-Electrophile Coupling

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(18), С. 9951 - 9958

Опубликована: Май 1, 2023

Carbon-heteroatom bonds, most often amide and ester are the standard method to link together two complex fragments because carboxylic acids, amines, alcohols ubiquitous reactions reliable. However, C-N C-O linkages a metabolic liability they prone hydrolysis. While C(sp

Язык: Английский

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PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

Molecules, Год журнала: 2023, Номер 28(10), С. 4014 - 4014

Опубликована: Май 10, 2023

A potential therapeutic strategy to treat conditions brought on by the aberrant production of a disease-causing protein is emerging for targeted breakdown using PROTACs technology. Few medications now in use are tiny, component-based and utilize occupancy-driven pharmacology (MOA), which inhibits function short period time temporarily alter it. By utilizing an event-driven MOA, proteolysis-targeting chimeras (PROTACs) technology introduces revolutionary tactic. Small-molecule-based heterobifunctional hijack ubiquitin–proteasome system trigger degradation target protein. The main challenge PROTAC’s development facing find potent, tissue- cell-specific PROTAC compounds with favorable drug-likeness standard safety measures. ways increase efficacy selectivity focus this review. In review, we have highlighted most important discoveries related proteins PROTACs, new approaches boost proteolysis’ effectiveness development, promising future directions medicine.

Язык: Английский

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Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera

Journal of Biomedical Science, Год журнала: 2023, Номер 30(1)

Опубликована: Апрель 26, 2023

Amyotrophic lateral sclerosis (ALS) associated with TAR DNA-binding protein 43 (TDP-43) aggregation has been considered as a lethal and progressive motor neuron disease. Recent studies have shown that both C-terminal TDP-43 (C-TDP-43) aggregates oligomers were neurotoxic pathologic agents in ALS frontotemporal lobar degeneration (FTLD). However, misfolding long an undruggable target by applying conventional inhibitors, agonists, or antagonists. To provide this unmet medical need, we aim to degrade these proteins designing series of proteolysis targeting chimeras (PROTACs) against C-TDP-43.By filter trap assay, western blotting, microscopy imaging, the degradation efficiency C-TDP-43 was studied Neuro-2a cells overexpressing eGFP-C-TDP-43 mCherry-C-TDP-43. The cell viability characterized alarmarBlue assay. beneficial disaggregating effects PROTAC examined YFP-C-TDP-43 transgenic C. elegans motility assay confocal microscopy. impact on oligomeric intermediates monitored fluorescence lifetime imaging size exclusion chromatography co-expressing mCherry-C-TDP-43.Four PROTACs different linker lengths synthesized characterized. Among chimeras, 2 decreased relieved C-TDP-43-induced cytotoxicity without affecting endogenous TDP-43. We showed bound E3 ligase initiate ubiquitination proteolytic degradation. By advanced microscopy, it further compactness population oligomers. In addition cellular model, also improved reducing nervous system.Our study demonstrated dual-targeting capacity newly-designed reduce their neurotoxicity, which shed light potential drug development for well other neurodegenerative diseases.

Язык: Английский

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Development of Substituted Phenyl Dihydrouracil as the Novel Achiral Cereblon Ligands for Targeted Protein Degradation

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(4), С. 2904 - 2917

Опубликована: Фев. 7, 2023

Glutarimides such as thalidomide, pomalidomide, and lenalidomide are the most frequently used ligands to recruit E3 ubiquitin ligase cereblon (CRBN) for development of proteolysis-targeting chimeras (PROTACs). Due rapid spontaneous racemization glutarimides, CRBN-recruiting PROTACs synthesized a mixture racemates or diastereomers. Since (S)-enantiomer is primarily responsible binding CRBN, existence largely inactive (R)-enantiomer complicates drug process. Herein, we report that substituted achiral phenyl dihydrouracil (PDHU) can be novel class CRBN PROTACs. Although parent PDHU has minimal affinity found some PDHUs had comparable lenalidomide. Structural modeling provided further understanding molecular interactions between CRBN. also have greater stability than Finally, potent BRD4 degraders were developed by employing trisubstituted PDHUs.

Язык: Английский

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E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(5), С. 3173 - 3194

Опубликована: Фев. 23, 2023

Ubiquitination is a key post-translational modification of proteins, affecting the regulation multiple cellular processes. Cells are equipped with over 600 ubiquitin orchestrators, called E3 ligases, responsible for directing covalent attachment to substrate proteins. Due their regulatory role in cells, significant efforts have been made discover ligands ligases. The recent emergence proteolysis targeting chimera (PROTAC) and molecular glue degrader (MGD) modalities has further increased interest ligases as drug targets. This perspective focuses on how fragment based lead discovery (FBLD) methods used new this important target class. In some cases these led clinical candidates; others, they provided tools deepening our understanding ligase biology. Recently, FBLD-derived inspired design PROTACs that able artificially modulate protein levels cells.

Язык: Английский

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PROTACs: A novel strategy for cancer drug discovery and development

MedComm, Год журнала: 2023, Номер 4(3)

Опубликована: Май 29, 2023

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: small molecule that binds to target protein, an E3 ligase ligand (consisting and its recruiter), chemical linker hooks first two components together. In the past 20 years, we have witnessed advancement multiple degraders into clinical trials anticancer therapies. However, one major challenges is only very limited number recruiters are currently available as targeted protein degradation (TPD), although human genome encodes more than 600 ligases. Thus, there urgent need identify additional effective TPD applications. this review, summarized existing RING-type ubiquitin their act ligands application discovery. We believe review could serve reference future development efficient cancer discovery development.

Язык: Английский

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