Advancing Strategies for Proteolysis-Targeting Chimera Design

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(4), P. 2308 - 2329

Published: Feb. 14, 2023

Proteolysis-targeting chimeras (PROTACs) have shown great therapeutic potential by degrading various disease-causing proteins, particularly those related to tumors. Therefore, the introduction of PROTACs has ushered in a new chapter antitumor drug development, marked significant advances over recent years. Herein, we describe developments PROTAC technology, focusing on design strategy, development workflow, and future outlooks. We also discuss opportunities challenges for research.

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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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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Developments of CRBN-based PROTACs as potential therapeutic agents

European Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 225, P. 113749 - 113749

Published: Aug. 10, 2021

Language: Английский

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Discovery of Potent PROTACs Targeting EGFR Mutants through the Optimization of Covalent EGFR Ligands

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(6), P. 4709 - 4726

Published: March 7, 2022

Drug resistance caused by epidermal growth factor receptor (EGFR) mutation has largely limited the clinical use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) for treatment non-small-cell lung cancer (NSCLC). Herein, to overcome intractable problem drug resistance, proteolysis targeting chimeras (PROTACs) mutants were developed optimizing covalent ligands. Covalent or reversible pyrimidine- purine-containing PROTACs designed, synthesized, and evaluated. As a consequence, PROTAC CP17, with novel ligand, was discovered as highly potent degrader against EGFRL858R/T790M EGFRdel19, reaching lowest DC50 values among all reported EGFR-targeting PROTACs. Furthermore, CP17 exhibited excellent cellular activity H1975 HCC827 cell lines high selectivity. Mechanism investigation indicated that lysosome involved in degradation process. Importantly, binding strategy proven be an effective approach design EGFRL858R/T790M, which laid practical foundation further development

Language: Английский

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Recent Advances in PROTACs for Drug Targeted Protein Research

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(18), P. 10328 - 10328

Published: Sept. 7, 2022

Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule. Typically, PROTAC consists of two terminals which are the ligand protein interest (POI) and specific E3 ubiquitin ligase, respectively, via suitable linker. degradation target performed through ubiquitin-proteasome system (UPS). The general process that binds to ligase form ternary complex label with ubiquitination. ubiquitinated recognized degraded by proteasome in cell. At present, PROTAC, as new type drug, has been developed degrade variety cancer proteins other disease proteins, shown good curative effects on diseases. For example, PROTACs targeting AR, BR, BTK, Tau, IRAK4, have unprecedented clinical efficacy cancers, neurodegenerative diseases, inflammations, fields. Recently, entered phase rapid development, opening field for biomedical research development. This paper reviews various fields targeted recent years summarizes prospects hot targets indications PROTAC.

Language: Английский

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Importance of Three-Body Problems and Protein–Protein Interactions in Proteolysis-Targeting Chimera Modeling: Insights from Molecular Dynamics Simulations

Journal of Chemical Information and Modeling, Journal Year: 2022, Volume and Issue: 62(3), P. 523 - 532

Published: Jan. 27, 2022

Proteolysis-targeting chimeras (PROTACs) are a class of bifunctional molecules that can induce the ubiquitin degradation its target protein by hijacking E3 ligase to form protein-PROTAC-E3 ternary complex. Its underlying principle has inspired development wide range degraders similar or beyond PROTACs in recent years. The formation complexes is key success PROTAC-induced degradation. Nevertheless, lack effective complex modeling techniques limited application computer-aided drug discovery tools this emerging and fast developing new land industry. Thus, study, we explored more physically sound molecular dynamics simulation mechanics combined with generalized Born surface area continuum solvation (MM/GBSA) method solve three-body problem PROTAC modeling. We first verified accuracy our approach using series known Brd4 BD2 degraders. calculated binding energy showed good correlation experimental Kd values. unique property, namely, α value, for was also accurately performed best knowledge. results demonstrated importance protein–protein interactions modeling, either qualitatively quantitatively. Finally, standing on earlier docking-based approaches, protocol applied as rescoring function pose prediction. notable improvement reranking initial poses generated from modified Rosetta method, which reportedly one among handful approaches available field. hope work could provide practical insights study design other

Language: Английский

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PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

Molecules, Journal Year: 2023, Volume and Issue: 28(10), P. 4014 - 4014

Published: May 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.

Language: Английский

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Applications and prospects of cryo-EM in drug discovery

Military Medical Research, Journal Year: 2023, Volume and Issue: 10(1)

Published: March 6, 2023

Abstract Drug discovery is a crucial part of human healthcare and has dramatically benefited lifespan life quality in recent centuries, however, it usually time- effort-consuming. Structural biology been demonstrated as powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) emerging the mainstream structure determination biomacromolecules past decade received increasing attention from pharmaceutical industry. Although cryo-EM still limitations resolution, speed throughput, growing number innovative drugs are being developed with help cryo-EM. Here, we aim provide an overview how techniques applied facilitate discovery. The development typical workflow technique will be briefly introduced, followed by its specific applications structure-based design, fragment-based discovery, proteolysis targeting chimeras, antibody repurposing. Besides cryo-EM, innovation involves other state-of-the-art such artificial intelligence (AI), which increasingly active diverse areas. combination AI provides opportunity minimize automation, throughput interpretation medium-resolution maps, tends new direction future rapid make indispensable modern

Language: Английский

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