Chemical degradation of BTK/TEC as a novel approach to inhibit platelet function

Trory, Justin S; Munkacsi, Attila; Śledź, Kamila M.; Vautrinot, Jordan; Goudswaard, Lucy J; Jackson, Molly L; Heesom, Kate J; Moore, Samantha; Poole, Alastair W.; Nabet, Behnam; Aggarwal, Varinder K.; Hers, Ingeborg

doi:10.1182/bloodadvances.2022008466

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The Expanding Toolbox For In Vivo Studies Of Platelet Contri...1

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2025

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Cited by 3 publications

(1 citation statement)

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“…Table 1 provides a critical overview of these experimental approaches. In addition to these in vivo methods, approaches to alter human platelets are also useful for mechanistic studies, including recently-developed in vitro approaches to genetically or pharmacologically alter protein abundance (Suzuki et al, 2020;Trory et al, 2022).…”

Section: The Expanding Toolbox For In Vivo Studies Of Platelet Contri...mentioning

confidence: 99%

Investigating and imaging platelets in inflammation

Cleary¹,

Conrad²

2023

The International Journal of Biochemistry & Cell Biology

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Section: The Expanding Toolbox For In Vivo Studies Of Platelet Contri...mentioning

confidence: 99%

Investigating and imaging platelets in inflammation

Cleary¹,

Conrad²

2023

The International Journal of Biochemistry & Cell Biology

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Safety assessment and exploration of the mechanism of toxic effects of diallyl trisulfide: Based on acute and subacute toxicity and proteomics experiments

Wu,

Tu,

et al. 2025

Journal of Ethnopharmacology

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PROTACs in platelets: emerging antithrombotic strategies and future perspectives

Trory,

Vautrinot,

May

et al. 2024

Current Opinion in Hematology

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Purpose of review Proteolysis-targeted chimeras (PROTACs) are heterobifunctional compounds that selectively target proteins for degradation and are an emerging therapeutic modality to treat diseases such as cancer and neurodegenerative disorders. This review will widen the area of application by highlighting the ability of PROTACs to remove proteins from the anucleate platelets and evaluate their antithrombotic potential. Recent findings Proteomic and biochemical studies demonstrated that human platelets possess the Ubiquitin Proteasomal System as well as the E3 ligase cereblon (CRBN) and therefore may be susceptible to PROTAC-mediated protein degradation. Recent findings confirmed that CRBN ligand-based PROTACs targeting generic tyrosine kinases, Btk and/or Fak lead to efficacious and selective protein degradation in human platelets. Downregulation of Btk, a key player involved in signalling to thrombosis, but not haemostasis, resulted in impaired in-vitro thrombus formation. Summary Platelets are susceptible to targeted protein degradation by CRBN ligand-based PROTACs and have limited ability to resynthesise proteins, ensuring long-term downregulation of target proteins. Therefore, PROTACs serve as an additional research tool to study platelet function and offer new therapeutic potential to prevent thrombosis. Future studies should focus on enhancing cell specificity to avoid on-target side effects on other blood cells.

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Chemical degradation of BTK/TEC as a novel approach to inhibit platelet function

Abstract: Visual Abstract

Cited by 3 publications

References 15 publications

Investigating and imaging platelets in inflammation

Investigating and imaging platelets in inflammation

Safety assessment and exploration of the mechanism of toxic effects of diallyl trisulfide: Based on acute and subacute toxicity and proteomics experiments

PROTACs in platelets: emerging antithrombotic strategies and future perspectives

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