Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Язык: Английский

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Annual review of PROTAC degraders as anticancer agents in 2022

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 267, С. 116166 - 116166

Опубликована: Янв. 25, 2024

Язык: Английский

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Recent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(13), С. 8428 - 8440

Опубликована: Июнь 15, 2023

Proteolysis-targeting chimera (PROTAC) technology represents a novel and promising modality for targeted protein degradation with transformative implications the clinical management of various diseases. Despite notable advantages, possibility on-target off-tumor toxicity in healthy cells critical challenge to applications cancer treatment. Researchers are currently exploring strategies enhance activity cell-selective manner minimize undesirable side effects. In this Perspective, we highlight innovative approaches prodrug-based PROTACs (pro-PROTACs) that facilitate tumor-targeted release. The development such may further expand range potential PROTAC within drug development.

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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Discovery of a PROTAC degrader for METTL3-METTL14 complex

Cell chemical biology, Год журнала: 2024, Номер 31(1), С. 177 - 183.e17

Опубликована: Янв. 1, 2024

Язык: Английский

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Targeting the undruggables—the power of protein degraders

Science Bulletin, Год журнала: 2024, Номер 69(11), С. 1776 - 1797

Опубликована: Март 29, 2024

Undruggable targets typically refer to a class of therapeutic that are difficult target through conventional methods or have not yet been targeted, but great clinical significance. According statistics, over 80% disease-related pathogenic proteins cannot be targeted by current treatment methods. In recent years, with the advancement basic research and new technologies, development various technologies mechanisms has brought perspectives overcome challenging drug targets. Among them, protein degradation technology is breakthrough strategy for This can specifically identify directly degrade utilizing inherent pathways within cells. form includes types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting (AUTAC), (AUTOTAC), degrader-antibody conjugate (DAC). article systematically summarizes application in degraders Finally, looks forward future direction prospects technology.

Язык: Английский

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Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders

Cell chemical biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer

Nature Cancer, Год журнала: 2025, Номер 6(1), С. 24 - 40

Опубликована: Янв. 30, 2025

Язык: Английский

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Antiviral PROTACs: Opportunity borne with challenge

Cell Insight, Год журнала: 2023, Номер 2(3), С. 100092 - 100092

Опубликована: Март 27, 2023

Proteolysis targeting chimera (PROTAC) degradation of pathogenic proteins by hijacking the ubiquitin-proteasome-system has become a promising strategy in drug design. The overwhelming advantages PROTAC technology have ensured rapid and wide usage, multiple PROTACs entered clinical trials. Several antiviral been developed with bioactivities against various viruses. However, number reported is far less than that other diseases, e.g., cancers, immune disorders, neurodegenerative possibly because common deficiencies (e.g., limited available ligands poor membrane permeability) plus complex mechanism involved high tendency viral mutation during transmission replication, which may challenge successful development effective PROTACs. This review highlights important advances this rapidly growing field critical limitations encountered developing analyzing current status representative examples PROTAC-like agents. We also summarize analyze general principles strategies for design optimization intent indicating potential strategic directions future progress.

Язык: Английский

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Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(4), С. 104572 - 104572

Опубликована: Март 2, 2023

Post-translational modifications (PTMs) regulate all aspects of protein function. Therefore, upstream regulators PTMs, such as kinases, acetyltransferases, or methyltransferases, are potential therapeutic targets for human diseases, including cancer. To date, multiple inhibitors and/or agonists these PTM in clinical use, while others still development. However, control not only the PTMs disease-related target proteins but also other disease-irrelevant substrate proteins. Thus, nontargeted perturbing activities may introduce unwanted off-target toxicity issues that limit use drugs successful applications. alternative solely a specific disease-relevant provide more precise effect treating disease with relatively low side effects. this end, chemically induced proximity has recently emerged powerful research tool, and several chemical inducers (CIPs) have been used to ubiquitination, phosphorylation, acetylation, glycosylation. These CIPs high be translated into examples PROTACs MGDs now trials. Hence, need developed cover types methylation palmitoylation, thus providing full spectrum tools basic application effective cancer treatment. Eukaryotic cells rely on posttranslational activity, stability, subcellular localization, protein–protein interactions (PPIs) (1Beltrao P. Albanèse V. Kenner L.R. Swaney D.L. Burlingame A. Villén J. et al.Systematic functional prioritization modifications.Cell. 2012; 150: 413-425Abstract Full Text PDF PubMed Scopus (306) Google Scholar, 2Walsh G. Jefferis R. context proteins.Nat. Biotechnol. 2006; 24: 1241-1252Crossref (742) 3Deribe Y.L. Pawson T. Dikic I. signal integration.Nat. Struct. Mol. Biol. 2010; 17: 666-672Crossref (541) 4Peng Y. Liu H. Long mitochondrial metabolic enzymes cancer.Free Radic. 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Язык: Английский

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