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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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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Modified nucleic acid aptamers: development, characterization, and biological applications

Trends in biotechnology, Год журнала: 2023, Номер 41(11), С. 1360 - 1384

Опубликована: Июнь 10, 2023

Язык: Английский

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Recent Studies and Progress in the Intratumoral Administration of Nano-Sized Drug Delivery Systems

Nanomaterials, Год журнала: 2023, Номер 13(15), С. 2225 - 2225

Опубликована: Июль 31, 2023

Over the last 30 years, diverse types of nano-sized drug delivery systems (nanoDDSs) have been intensively explored for cancer therapy, exploiting their passive tumor targetability with an enhanced permeability and retention effect. However, systemic administration has aroused some unavoidable complications, including insufficient tumor-targeting efficiency, side effects due to undesirable biodistribution, carrier-associated toxicity. In this review, recent studies advancements in intratumoral nanoDDS are generally summarized. After identifying factors be considered enhance therapeutic efficacy administration, experimental results on application various therapies discussed. Subsequently, reports clinical addressed short. Intratumoral is proven its versatility tumor-specific accumulation agents modalities. Specifically, it can improve poor bioavailability by increasing concentration, while minimizing effect highly toxic restricting normal tissues. expand area potent ability relieve toxicities nanoDDSs.

Язык: Английский

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Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods

Journal of Chemical Information and Modeling, Год журнала: 2023, Номер 63(17), С. 5408 - 5432

Опубликована: Авг. 21, 2023

The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with inhibition. Recent advancements in the biotech and pharmaceutical sectors have led development compounds that are currently human trials, some showing promising clinical results. However, use computational tools TPD still limited, as it has distinct characteristics traditional drug design methods. involves creating a ternary structure (protein-degrader-ligase) responsible for biological function, such ubiquitination subsequent proteasomal degradation, which depends on spatial orientation interest (POI) relative E2-loaded ubiquitin. Modeling this necessitates unique blend initially developed small molecules (e.g., docking) biologics protein-protein interaction modeling). Additionally, degrader molecules, particularly heterobifunctional degraders, generally larger than conventional molecule drugs, leading challenges determining drug-like properties like solubility permeability. Furthermore, catalytic nature makes occupancy-based modeling insufficient. consists multiple interconnected yet steps, POI binding, E3 ligase interactions, ubiquitination, along properties. A comprehensive set needed address dynamic induced proximity complex implications ubiquitination. In Perspective, we discuss current state TPD. We start by describing series steps involved process experimental methods used characterize them. Then, delve into detailed analysis employed also present an integrative proven successful impact project decisions. Finally, examine future prospects areas greatest potential impact.

Язык: Английский

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Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases

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

Опубликована: Ноя. 13, 2023

Abstract Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and co-activators. Deregulation these regulatory molecules is associated with state transitions, which turn accountable for diverse maladies, including developmental disorders, metabolic most significantly, cancer. A decade back factors, key enablers disease development, were historically viewed as ‘undruggable’; however, intervening years, a wealth literature validated they can be targeted indirectly through transcriptional co-activators, their confederates various physiological molecular processes. These along have ability to initiate modulate genes necessary normal functions, whereby, deregulation such may foster tissue-specific phenotype. Hence, it essential analyze how co-activators specific multilateral processes coordination other factors. The proposed review attempts elaborate an in-depth account involvement regulation, context-specific contributions pathophysiological conditions. This also addresses issue has not been dealt comprehensive manner hopes direct attention towards future research will encompass patient-friendly therapeutic strategies, where drugs targeting enhanced benefits reduced side effects. Additional insights into currently available interventions constraints eventually reveal multitudes advanced targets aiming amelioration good patient prognosis.

Язык: Английский

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Leveraging aptamers for targeted protein degradation

Trends in Pharmacological Sciences, Год журнала: 2023, Номер 44(11), С. 776 - 785

Опубликована: Июнь 26, 2023

Язык: Английский

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Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy

Acta Pharmacologica Sinica, Год журнала: 2024, Номер 45(8), С. 1740 - 1751

Опубликована: Апрель 12, 2024

Язык: Английский

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An engineered DNA aptamer-based PROTAC for precise therapy of p53-R175H hotspot mutant-driven cancer

Science Bulletin, Год журнала: 2024, Номер 69(13), С. 2122 - 2135

Опубликована: Май 18, 2024

Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various types. Despite extensive efforts, absence a druggable active site small molecules has rendered these mutants therapeutically non-actionable. Here we develop selective effective proteolysis-targeting chimera (PROTAC) p53-R175H, common hotspot with dominant-negative activity. Using novel iterative molecular docking-guided post-SELEX (systematic evolution ligands by exponential enrichment) approach, rationally engineer high-performance DNA aptamer improved affinity specificity p53-R175H. Leveraging this resulting as binder PROTACs, successfully developed p53-R175H degrader, named dp53m. dp53m induces ubiquitin-proteasome-dependent degradation while sparing wildtype p53. Importantly, demonstrates significant antitumor efficacy p53-R175H-driven cells both vitro vivo, without toxicity. Moreover, significantly synergistically improves sensitivity cisplatin, commonly used chemotherapy drug. These findings provide evidence potential therapeutic value cancers.

Язык: Английский

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Enzymatic Synthesis of TNA Protects DNA Nanostructures

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(13)

Опубликована: Фев. 7, 2024

Abstract Xeno‐nucleic acids (XNAs) are synthetic genetic polymers with improved biological stabilities and offer powerful molecular tools such as aptamers catalysts. However, XNA application has been hindered by a very limited repertoire of tool enzymes, particularly those that enable de novo synthesis. Here we report terminal deoxynucleotide transferase (TdT) catalyzes untemplated threose nucleic acid (TNA) synthesis at the 3’ terminus DNA oligonucleotide, resulting in DNA‐TNA chimera resistant to exonuclease digestion. Moreover, TdT‐catalyzed TNA extension supports one‐pot batch preparation biostable chimeric oligonucleotides, which can be used directly staple strands during self‐assembly origami nanostructures (DONs). Such TNA‐protected DONs show enhanced stability presence I, DNase I fetal bovine serum. This work not only expands available enzyme toolbox for manipulation, but also provides promising approach fabricate under physiological condition.

Язык: Английский

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