Design and Discovery of Silmitasertib-based Drugs as a Potential Casein Kinase II Inhibitor for Cholangiocarcinoma through Hybrid In-silico Ligand-Based Virtual Screening with Molecular Docking Method DOI Open Access

Pravin Tajane,

Nandu Kayande,

Avinash Bhosale

et al.

International Journal of Drug Delivery Technology, Journal Year: 2023, Volume and Issue: 13(04), P. 1514 - 1519

Published: Dec. 25, 2023

This research investigates the design and discovery of silmitasertib-based drugs as potential inhibitors casein kinase II (CK2) for cholangiocarcinoma using hybrid in-silico methods. The study employs a two-fold approach, including ligand-based virtual screening molecular docking, to assess inhibitory compounds. involves construction diverse compound library, followed by energy minimization conformational analysis, revealing set compounds with varied similarities silmitasertib. In parallel, CK2 model undergoes meticulous selection, validation, refinement through PDB REDO, showcasing significant improvements in quality. Molecular docking results highlight promising candidates, N-(2, 4, 6-trimethylphenyl) phenanthridin-6-amine (MCULE-1492185963-0) emerging lead superior binding characteristics compared approach demonstrates identifies further experimental validation. findings contribute valuable insights novel treatment, setting stage future clinical investigations

Language: Английский

Claudin-2 upregulation enhances intestinal permeability, immune activation, dysbiosis, and mortality in sepsis DOI Creative Commons
Takehiko Oami, Shabnam Abtahi, Takashi Shimazui

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(10)

Published: Feb. 27, 2024

Intestinal epithelial expression of the tight junction protein claudin-2, which forms paracellular cation and water channels, is precisely regulated during development in disease. Here, we show that small intestinal claudin-2 selectively upregulated septic patients. Similar changes occurred mice, where upregulation coincided with increased flux across pore pathway. In order to define significance these changes, sepsis was induced knockout (KO) wild-type (WT) mice. Sepsis-induced increases pathway permeability were prevented by KO. Moreover, deletion reduced interleukin-17 production T cell activation limited damage. These effects associated numbers neutrophils, macrophages, dendritic cells, bacteria within peritoneal fluid KO Most strikingly, dramatically enhanced survival sepsis. Finally, microbial less pathogenic mice as healthy WT injected cecal slurry collected from 24 h after far worse than Claudin-2 are, therefore, key intermediates contribute dysbiosis, damage, inflammation, ineffective pathogen control, mortality The striking impact on progression lethal cascade activated suggests may be an attractive therapeutic target

Language: Английский

Citations

15
Advances in pyrazolo[1,5-a]pyrimidines: synthesis and their role as protein kinase inhibitors in cancer treatment DOI Creative Commons

Terungwa H. Iorkula,

Osasere Jude-Kelly Osayawe,

Daniel A. Odogwu

et al.

RSC Advances, Journal Year: 2025, Volume and Issue: 15(5), P. 3756 - 3828

Published: Jan. 1, 2025

Pyrazolo[1,5- a ]pyrimidines are notable class of heterocyclic compounds with potent protein kinase inhibitor (PKI) activity, playing critical role in targeted cancer therapy.

Language: Английский

Citations

1
DCAF13-mediated K63-linked ubiquitination of RNA polymerase I promotes uncontrolled proliferation in Breast Cancer DOI Creative Commons

Zhi-Zhi Yang,

Bing Yang, Haiyan Yan

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 9, 2025

Hyperactivation of ribosome biogenesis (RiBi) drives cancer progression, yet the role RiBi-associated proteins (RiBPs) in breast (BC) is underexplored. In this study, we perform a comprehensive multi-omics analysis and reveal that assembly maturation factors (AMFs), subclass RiBPs, are upregulated at both RNA protein levels BC, correlating with poor patient outcomes. contrast, ribosomal (RPs) do not show systematic upregulation across various cancers, including BC. We further demonstrate oncogenic activation top AMF candidate DCAF13, enhances Pol I transcription promotes proliferation BC cells vitro vivo. Mechanistically, DCAF13 activity by facilitating K63-linked ubiquitination RPA194. This process stimulates global synthesis cell growth. Our findings uncover modification RPA194 regulates activity; dysregulated contributing to progression. causes excessive production, genome instability The authors investigate RiBPs cancer, highlighting like which regulating via

Language: Английский

Citations

0
Targeting the IKZF1/BCL-2 axis as a novel therapeutic strategy for treating acute T-cell lymphoblastic leukemia DOI Creative Commons
Juan Li,

Chunmei Ye,

Hui Li

et al.

Cancer Biology & Therapy, Journal Year: 2025, Volume and Issue: 26(1)

Published: Jan. 25, 2025

Objectives Acute T-cell lymphoblastic leukemia (T-ALL) is a severe hematologic malignancy with limited treatment options and poor long-term survival. This study explores the role of IKZF1 in regulating BCL-2 expression T-ALL.

Language: Английский

Citations

0
Interaction with IP6K1 supports pyrophosphorylation of substrate proteins by the inositol pyrophosphate 5-InsP7 DOI Open Access
Aisha Hamid, Jayashree S Ladke, Akruti Shah

et al.

Bioscience Reports, Journal Year: 2024, Volume and Issue: 44(10)

Published: Sept. 4, 2024

Inositol pyrophosphates (PP-InsPs) are a sub-family of water soluble inositol phosphates that possess one or more diphosphate groups. PP-InsPs can transfer their β-phosphate group to phosphorylated Ser residue generate pyrophosphorylated Ser. This unique post-translational modification occurs on residues lie in acidic stretches within an intrinsically disordered protein sequence. Serine pyrophosphorylation is dependent the presence Mg2+ ions, but does not require enzyme for catalysis. The mechanisms by which cells regulate PP-InsP-mediated still unknown. We performed mass spectrometry identify interactors IP6K1, responsible synthesis PP-InsP 5-InsP7. Interestingly, IP6K1 interacted with several proteins known undergo 5-InsP7-mediated pyrophosphorylation, including nucleolar NOLC1, TCOF and UBF1, AP3B1, β subunit AP3 adaptor complex. interactome also included CK2, kinase phosphorylates prior pyrophosphorylation. observe formation complex between catalytic α-subunit show disrupting binding AP3B1 lowers its vivo propose assembly substrate-CK2-IP6K would allow coordinated pre-phosphorylation target serine residue, provide mechanism this enzyme-independent modification.

Language: Английский

Citations

3
Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity DOI Open Access
Sushma Bartaula-Brevik,

Calum Leitch,

Maria Hernandez-Valladares

et al.

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(17), P. 5546 - 5546

Published: Aug. 25, 2023

Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It expressed primary acute myeloid leukemia cells (AML), but the expression varies between patients and highest for with favorable prognosis after intensive chemotherapy. We therefore investigated functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) AML derived from 80 consecutive patients. The showed dose-dependent antiproliferative proapoptotic that varied considerably A proteomic comparison showing weak versus strong inhibition differential proteins involved intracellular transport/cytoskeleton functions, an equivalent phosphoproteomic regulate RNA processing/function together increased activity casein kinase 2. Patients secondary AML, i.e., heterogeneous subset generally adverse previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by effect also specific mRNA profile interactome proteins. Furthermore, altered constitutive extracellular release several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), mediator levels presence AML-supporting bone marrow mesenchymal stem was then observed, especially AML. Finally, animal studies suggested inhibitor bafilomycin had limited toxicity, even when combined cytarabine. To conclude, has antileukemic this

Language: Английский

Citations

6
Targeting chaperone modifications: Innovative approaches to cancer treatment DOI Creative Commons
Mariah Stewart, Jonathan C. Schisler

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 107907 - 107907

Published: Oct. 1, 2024

Language: Английский

Citations

1
Preclinical activity of resazurin in acute myeloid leukaemia DOI Creative Commons
Trung Quang Ha, Vibeke Andresen, Bjarte Skoe Erikstein

et al.

British Journal of Haematology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 24, 2024

Summary Resazurin, a phenoxazine used in cell viability assays, acts vitro as an anti‐leukaemic compound through the production of cellular reactive oxygen species (ROS) resulting mitochondrial dysfunction and death. However, vivo tolerance efficacy resazurin cancer are unknown. In this study, we investigated effects acute myeloid leukaemia (AML). Resazurininduced death dose‐dependent manner AML lines reduced proliferation colony formation ex treated patient‐derived cells. Cells with dose for 72 h acquired more mature immunophenotype suggesting differentiation mechanism contributing to effect. optical imaging healthy mice demonstrated reduction resorufin within 30 min non‐detectable after 2 h, supporting dosing twice daily optimal. subcutaneous orthotopic models MV4‐11 NOD/SCID IL2rγ null mice, anti‐tumour increased survival were found at level 75 mg/kg without observed toxicity. Our results suggest that represents novel experimental therapeutic treatment AML.

Language: Английский

Citations

0
Unlocking reproducible transcriptomic signatures for acute myeloid leukaemia: Integration, classification and drug repurposing DOI Creative Commons
Haoran Chen,

Jinqi Lu,

Zining Wang

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(17)

Published: Sept. 1, 2024

Acute myeloid leukaemia (AML) is a highly heterogeneous disease, which lead to various findings in transcriptomic research. This study addresses these challenges by integrating 34 datasets, including 26 control groups, 6 prognostic datasets and 2 single-cell RNA sequencing (scRNA-seq) identify 10,000 AML-related genes (ARGs). We focused on with low variability high consistency successfully discovered 191 AML signatures (ASs). Leveraging machine learning techniques, specifically the XGBoost model our custom framework, we classified subtypes both scRNA-seq bulk RNA-seq data, complementing ELN2022 classification approach. Our research also identified promising treatments for through drug repurposing, solasonine showing potential efficacy high-risk patients, supported molecular docking analyses. To enhance reproducibility customizability, developed CSAMLdb, user-friendly database platform. It facilitates reuse personalized analysis of nearly all results obtained this research, single-gene prognostics, multi-gene scoring, enrichment analysis, risk assessment, repositioning literature abstract named entity recognition. CSAMLdb available at http://www.csamldb.com.

Language: Английский

Citations

0
Epithelial membrane protein 1 in human cancer: a potential diagnostic biomarker and therapeutic target DOI

Yuxin Xie,

Feng Wu, Zhe Chen

et al.

Biomarkers in Medicine, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 11

Published: Oct. 29, 2024

Epithelial membrane protein 1 (EMP1) is a member of the small hydrophobic subfamily. EMP1 aberrantly expressed in various tumor tissues and governs multiple cellular behaviors (e.g., proliferation, differentiation, migration). The resultant regulation cancer pathway responsible for metastasis cells determines risk malignant progression. This review provides an updated overview as either oncogene or suppressor contingent on type summarizes its upstream regulators downstream target genes. systematic our current understanding role development, including critical functional mechanisms implications potential use biomarker therapeutic target.

Language: Английский

Citations

0