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

Science Bulletin, Journal Year: 2024, Volume and Issue: 69(13), P. 2122 - 2135

Published: May 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.

Language: Английский

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What influences the activity of Degrader−Antibody conjugates (DACs)

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 268, P. 116216 - 116216

Published: Feb. 3, 2024

Language: Английский

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Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

Journal of Cellular Physiology, Journal Year: 2024, Volume and Issue: 239(5)

Published: March 19, 2024

Abstract Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin‐proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into various types of PROTACs, such as peptide‐based, nucleic acid‐based, and small molecule each addressing distinct challenges degradation. It also discusses innovative strategies like bridged PROTACs conditional switch‐activated offering precise targeting previously “undruggable” proteins. The potential extends beyond oncology, with ongoing research technological advancements needed maximize their potential. Future progress this field relies on interdisciplinary collaboration integration advanced computational tools open new treatment avenues across diseases.

Language: Английский

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Targeted degradation of membrane and extracellular proteins with LYTACs

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Language: Английский

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High‐Throughput Miniaturized Synthesis of PROTAC‐Like Molecules

Small, Journal Year: 2024, Volume and Issue: 20(26)

Published: Jan. 22, 2024

The development of miniaturized high-throughput in situ screening platforms capable handling the entire process drug synthesis to final is essential for advancing discovery future. In this study, an approach based on combinatorial solid-phase synthesis, enabling efficient libraries proteolysis targeting chimeras (PROTACs) array format presented. This on-chip platform allows direct biological without need transfer steps. UV-induced release target molecules into individual droplets facilitates further experimentation. Utilizing a mitogen-activated protein kinase kinases (MEK1/2) degrader as template, series 132 novel PROTAC-like synthesized using Ugi reaction. These compounds are characterized various methods, including matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) imaging, while consuming only few milligrams starting materials total. Furthermore, feasibility culturing cancer cells modified spots and quantifying effect MEK suppression demonstrated. lays foundation potent PROTACs potential anticancer activity offers accelerating by integrating steps same array.

Language: Английский

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Journey of Von Hippel-Lindau (VHL) E3 ligase in PROTACs design: From VHL ligands to VHL-based degraders

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 265, P. 116041 - 116041

Published: Dec. 13, 2023

Language: Английский

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Potential of the nanoplatform and PROTAC interface to achieve targeted protein degradation through the Ubiquitin–Proteasome system

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116168 - 116168

Published: Feb. 1, 2024

Language: Английский

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Targeted degradation of VEGF with bispecific aptamer-based LYTACs ameliorates pathological retinal angiogenesis

Theranostics, Journal Year: 2024, Volume and Issue: 14(13), P. 4983 - 5000

Published: Jan. 1, 2024

Neovascular ocular diseases (NODs) represent the leading cause of visual impairment globally. Despite significant advances in anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF), persistent challenges remain prevalent. As a proof-of-concept study, we herein demonstrate effectiveness targeted degradation VEGF with bispecific aptamer-based lysosome-targeting chimeras (referred to as VED-LYTACs).

Language: Английский

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Powering up targeted protein degradation through active and passive tumour-targeting strategies: Current and future scopes

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 263, P. 108725 - 108725

Published: Sept. 24, 2024

Language: Английский

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Multifaceted roles of UFMylation in health and disease

Acta Pharmacologica Sinica, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Language: Английский

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