Search results for "protein kinase inhibitor"

IKK-β inhibitors: An analysis of drug–receptor interaction by using Molecular Docking and Pharmacophore 3D-QSAR approaches

2010

Abstract The IKK kinases family represents a thrilling area of research because of its importance in regulating the activity of NF-kB transcription factors. The discovery of the central role played by IKK-β in the activation of transcription in response to apoptotic or inflammatory stimuli allowed to considerate its modulation as a promising tool for the treatment of chronic inflammation and cancer. To date, several IKK-β inhibitors have been discovered and tested. In this work, an analysis of the interactions between different classes of inhibitors and their biological target was performed, through the application of Molecular Docking and Pharmacophore/3D-QSAR approaches to a set of 141 in…

A Computational Study of the Protein-Ligand Interactions in CDK2 Inhibitors: Using Quantum Mechanics/Molecular Mechanics Interaction Energy as a Pred…

2006

ABSTRACT: We report a combined quantum mechanics/molecular mechanics (QM/MM) study to determine the protein-ligand interaction energy between CDK2 (cyclin-dependent kinase 2) and five inhibitors with the N2 -substituted 6-cyclohexylmethoxypurine scaffold. The computational results in this work show that the QM/MM interaction energy is strongly correlated to the biological activity and can be used as a predictor, at least within a family of substrates. A detailed analysis of the protein-ligand structures obtained from molecular dynamics simulations shows specific interactions within the active site that, in some cases, have not been reported before to our knowledge. The computed interaction …

Inhibition of Eimeria tenella CDK-related kinase 2: From target identification to lead compounds.

2010

Apicomplexan parasites encompass several human- and animal-pathogenic protozoans such as Plasmodium falciparum, Toxoplasma gondii, and Eimeria tenella. E. tenella causes coccidiosis, a disease that afflicts chickens, leading to tremendous economic losses to the global poultry industry. The considerable increase in drug resistance makes it necessary to develop new therapeutic strategies against this parasite. Cyclin-dependent kinases (CDKs) are key molecules in cell-cycle regulation and are therefore prominent target proteins in parasitic diseases. Bioinformatics analysis revealed four potential CDK-like proteins, of which one—E. tenella CDK-related kinase 2 (EtCRK2)—has already been charact…

PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets

2022

Funding Information: ACKNOWLEDGMENTS. We would like to thank Dr. Tuomas Tammela and Dr. Monika Ehnmann for providing RMS cell lines and Dr. Jenny Högström for discussions and comments during the project. Kirsi Mattinen, Jefim Brodkin, Maxime Laird, Manon Gruchet, Ilse Paetau, Tanja Laakkonen, and Tapio Tainola are acknowledged for their excellent technical help. We also thank the Laboratory Animal Center at the University of Helsinki for expert animal care, the Biomedicum Imaging Unit for microscope support, the Biomedicum Functional Genomics Unit for the RNAseq experiments and the FIMM Technology Centre High Throughput Biomedicine for the drug sensitivity and resistance testing. Our first …

Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition

2020

Abstract The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and provides a potential opportunity for treatment of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. In this study, transcriptional profiling after pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expression, with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being the most pronounced. Combining menin-MLL inhibition with specific small-molecule kinase inhibitors…

Extrahepatic spread of hepatocellular carcinoma

2012

Hepatocellular carcinoma (HCC) is a major health problem. The treatment of HCC depends on the tumour stage and on the severity of underlying cirrhosis, however, a majority of HCC patients have advanced disease at presentation. In recent years extra-hepatic spread (ES) of HCC seems to have been observed more frequently than in the past even if few data exist in literature on prevalence, clinical presentation and prognosis of patients with HCC ES. Aim of this brief review is underline the main concerns, pitfalls and warnings in practicing with these patients. ES of HCC are not rare, and the probability of finding ES is higher in patients with advanced intra-hepatic HCC. The more frequent ES s…

Targeted Therapies in Hepatocellular Carcinoma

2014

Abstract: The onset of hepatocellular carcinoma (HCC) is related to the development of non-neoplastic liver disease, such as viral infections and cirrhosis. Even though patients with chronic liver diseases undergo clinical surveillance for early diagnosis of HCC, this cancer is often diagnosed in advanced stage. In this case locoregional treatment is not possible and systemic therapies are the best way to control it. Until now sorafenib, a Raf and multi-kinase inhibitor has been the best, choice to treat HCC systemically. It showed a survival benefit in multicenter phase III trials. However the proper patient setting to treat is not well defined, since the results in Child-Pugh B patients a…

Stereotactic Radiotherapy for the Treatment of Patients With Oligo-progressive Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth …

2020

Aim This retrospective observational study evaluated the role of hypo-fractionated stereotactic radiotherapy (SRT) in patients with oligo-progressive metastatic renal cell carcinoma (mRCC) treated with first-line oral tyrosine kinase inhibitors (TKI). Data on local control, delay of further progression, and safety are reported. Patients and methods Between January 2010 and December 2016, 28 patients with mRCC who showed oligo-progressive disease while receiving first-line pazopanib were treated with hypofractionated SRT to progressive metastatic sites to delay the change of systemic therapy. First and second progression-free survival (PFS-1 and PFS-2) were recorded, as well as objective res…

Low-dose ponatinib is a good option in chronic myeloid leukemia patients intolerant to previous TKIs.

2020

Multi-center observational study on the adherence, quality of life, and adverse events in lung cancer patients treated with tyrosine kinase inhibitor…

2020

Introduction Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. Methods Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and &…