PROTACs in platelets: emerging antithrombotic strategies and future perspectives DOI
Justin S. Trory, Jordan Vautrinot, Carl May

и другие.

Current Opinion in Hematology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 21, 2024

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

Язык: Английский

In vitro and in vivo ADME of heterobifunctional degraders: a tailored approach to optimize DMPK properties of PROTACs© DOI

Christine K. Maurer,

Zhizhou Fang, Christina Schindler

и другие.

RSC Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

This study suggests a tailored in vitro DMPK discovery assay cascade and frontloading vivo studies. It also underlines the need for inclusion of surrogate permeability descriptors experimentally determined values IVIVE CL int .

Язык: Английский

Процитировано

2

Identification of E3 ubiquitin ligase-associated prognostic genes and construction of a prediction model for uterine cervical cancer based on bioinformatics analysis DOI Creative Commons

Zhengchao Yan,

Jingwei Yu,

Shuyuan Wang

и другие.

Discover Oncology, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 31, 2024

E3 ligases are engaged in a variety of physiological processes within cells and use ubiquitin-labeled substrates to control their activity stability. Although some research has indicated that or particular have an impact on the treatment cervical cancer patients get after diagnosis, The exact purpose these enzymes occurrence evolution region (CC) is not clear. In order extract analyze relevant mRNA gene expression data as well clinical patient data, we used open databases. A reliable risk prediction model was developed by applying least absolute shrinkage selection operator (LASSO) technique conjunction with Cox regression analysis. Column-line plots were combined predictive model, GSE44001 dataset served external validation.Four models:proteasome (prosome, macropain) 26S subunit, non-ATPase, 14(PSMD14),proteasome alpha type, 4(PSMA4,),zinc finger BTB domain containing 16(ZBTB16),and ankyrin repeat 9(ANKRD9). Gene levels both healthy cancerous tissues been confirmed HPA database. Next, investigation focused immunological state tumor mutation load. high-risk group Cluster B had distinct immune cell infiltration worse prognosis. Additionally, KEGG GO analyses differentially expressed genes (DEGs) between high- low-risk groups performed, microenvironment (TME) investigations. Targeting may be efficient strategy treat (CC), according novel comprehensive ubiquitination ligase-associated presented.

Язык: Английский

Процитировано

1

Research progress of BRD4 in head and neck squamous cell carcinoma: Therapeutic application of novel strategies and mechanisms DOI
Jiao Tang, Huaqiu Chen,

Hengrui Fan

и другие.

Bioorganic & Medicinal Chemistry, Год журнала: 2024, Номер 113, С. 117929 - 117929

Опубликована: Сен. 19, 2024

Язык: Английский

Процитировано

1

Proteolysis Targeting Chimera Agents (PROTACs): New Hope for Overcoming the Resistance Mechanisms in Oncogene-Addicted Non-Small Cell Lung Cancer DOI Open Access
Nicoletta Cordani,

Daniele Nova,

Luca Sala

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(20), С. 11214 - 11214

Опубликована: Окт. 18, 2024

Non-small cell lung cancer (NSCLC) remains a disease with poor prognosis despite the advances in therapies. NSCLC actionable oncogenic alterations represent subgroup of diseases for which tyrosine kinase inhibitors (TKIs) have shown relevant and robust impact on prognosis, both early advanced stages. While introduction powerful TKIs increases ratio potentially curable patients, does develop resistance over time through either secondary mutations or bypass activating tracks. Therefore, new treatment strategies are being developed to overcome this inevitable prevent it, proteolysis targeting chimera agents (PROTACs) among them. They consist two linked molecules that bind target protein an E3 ubiquitin ligase causes ubiquitination degradation proteins interest. In paper, we review rationale PROTAC therapy current development PROTACs oncogene-addicted cancer. Moreover, critically analyze strengths limitations promising technique may help pave way future perspectives.

Язык: Английский

Процитировано

1

PROTACs in platelets: emerging antithrombotic strategies and future perspectives DOI
Justin S. Trory, Jordan Vautrinot, Carl May

и другие.

Current Opinion in Hematology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 21, 2024

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

Язык: Английский

Процитировано

0