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

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 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.

Language: Английский

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An overview of PROTACs: a promising drug discovery paradigm

Molecular Biomedicine, Journal Year: 2022, Volume and Issue: 3(1)

Published: Dec. 20, 2022

Abstract Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets being studied, and most works focus on their enzymatic functions. Unlike small molecules, inhibit whole biological function binding to inducing subsequent proteasomal degradation. compensate for limitations transcription factors, nuclear proteins, other scaffolding difficult handle with traditional small-molecule inhibitors. have successfully degraded diverse such BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 ARV-471 exhibited excellent efficacy clinical II trials. However, what appropriate PROTAC achieve better benefits than inhibitors not fully understood. how rationally design an efficient optimize it be orally effective poses big challenges researchers. In this review, we summarize features technology, analyze detail general principles designing PROTACs, discuss typical application different categories. addition, also introduce progress relevant trial results representative assess may face. Collectively, our studies provide references further PROTACs.

Language: Английский

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The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(3)

Published: March 1, 2023

Abstract Ubiquitination is one of the most important post‐translational modifications which plays a significant role in conserving homeostasis cellular proteins. In ubiquitination process, ubiquitin conjugated to target protein substrates for degradation, translocation or activation, dysregulation linked several diseases including various types cancers. E3 ligases are regarded as influential enzyme owing their ability select, bind and recruit ubiquitination. particular, pivotal cancer hallmarks pathways where they serve tumour promoters suppressors. The specificity coupled with implication engendered development compounds that specifically therapy. this review, we highlight such sustained proliferation via cell cycle progression, immune evasion promoting inflammation, apoptosis. addition, summarise application small treatment along significance targeting potential

Language: Английский

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Annual review of PROTAC degraders as anticancer agents in 2022

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116166 - 116166

Published: Jan. 25, 2024

Language: Английский

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Tracking the PROTAC degradation pathway in living cells highlights the importance of ternary complex measurement for PROTAC optimization

Cell chemical biology, Journal Year: 2023, Volume and Issue: 30(7), P. 753 - 765.e8

Published: June 25, 2023

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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Targeting the undruggables—the power of protein degraders

Science Bulletin, Journal Year: 2024, Volume and Issue: 69(11), P. 1776 - 1797

Published: March 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.

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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Rational Design, Synthesis, and Biological Evaluation of Novel c-Met Degraders for Lung Cancer Therapy

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Cellular-mesenchymal epithelial transition factor (c-Met) is an attractive target for treating multiple cancers. Despite plentiful c-Met inhibitors have been developed, some issues, including the acquired drug resistance to inhibitors, emerged hamper their application in clinical treatment. Degradation of offers opportunity solve these issues. In this study, we developed a series degraders, and optimal compound 22b can efficiently degrade with DC50 value 0.59 nM EBC-1 cells. Mechanistic studies revealed that induced degradation via proteasome-mediated pathway. addition, suppressed proliferation also apoptosis cells, outperforming corresponding inhibitor tepotinib. Importantly, showed favorable pharmacokinetic properties significantly tumor regression xenograft model without obvious toxicity. brief, study provided as novel degrader lung cancer therapy.

Language: Английский

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Nano Proteolysis Targeting Chimeras (PROTACs) with Anti‐Hook Effect for Tumor Therapy

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(37)

Published: July 24, 2023

Abstract Proteolysis targeting chimera (PROTAC) is an emerging pharmacological modality with innovated post‐translational protein degradation capabilities. However, off‐target induced unintended tissue effects and intrinsic “hook effect” hinder PROTAC biotechnology to be maturely developed. Herein, intracellular fabricated nano proteolysis chimeras (Nano‐PROTACs) a center‐spoke network for achieving efficient dose‐dependent in tumor reported. The precursors are triggered by higher GSH concentrations inside cells, which subsequently situ self‐assemble into Nano‐PROTACs through intermolecular hydrogen bond interactions. fibrous can form effective polynary complexes E3 ligases multi‐binding sites, “anti‐hook effect”. generality efficacy of validated degrading variable interest (POI) such as epidermal growth factor receptor (EGFR) androgen (AR) wide‐range manner 95 % rate long‐lasting potency up 72 h vitro. Significantly, achieve vivo 79 inhibition A549 LNCap xenograft mice models, respectively. Taking advantages self‐assembly strategy, the provide generalizable platform promote precise clinical translational application PROTAC.

Language: Английский

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