Dataset Information

Identification of potent Yes1 kinase inhibitors using a library screening approach.

ABSTRACT: Yes1 kinase has been implicated as a potential therapeutic target in a number of cancers including melanomas, breast cancers, and rhabdomyosarcomas. Described here is the development of a robust and miniaturized biochemical assay for Yes1 kinase that was applied in a high throughput screen (HTS) of kinase-focused small molecule libraries. The HTS provided 144 (17% hit rate) small molecule compounds with IC?? values in the sub-micromolar range. Three of the most potent Yes1 inhibitors were then examined in a cell-based assay for inhibition of cell survival in rhabdomyosarcoma cell lines. Homology models of Yes1 were generated in active and inactive conformations, and docking of inhibitors supports binding to the active conformation (DFG-in) of Yes1. This is the first report of a large high throughput enzymatic activity screen for identification of Yes1 kinase inhibitors, thereby elucidating the polypharmacology of a variety of small molecules and clinical candidates.

SUBMITTER: Patel PR

PROVIDER: S-EPMC3769177 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of potent Yes1 kinase inhibitors using a library screening approach.

Patel Paresma R PR Sun Hongmao H Li Samuel Q SQ Shen Min M Khan Javed J Thomas Craig J CJ Davis Mindy I MI

Bioorganic & medicinal chemistry letters 20130529 15

Yes1 kinase has been implicated as a potential therapeutic target in a number of cancers including melanomas, breast cancers, and rhabdomyosarcomas. Described here is the development of a robust and miniaturized biochemical assay for Yes1 kinase that was applied in a high throughput screen (HTS) of kinase-focused small molecule libraries. The HTS provided 144 (17% hit rate) small molecule compounds with IC₅₀ values in the sub-micromolar range. Three of the most potent Yes1 inhibitors were then e ...[more]

PMID: 23787099

Similar Datasets

Project description:NIMA related Kinases (NEK7) plays an important role in spindle assembly and mitotic division of the cell. Over expression of NEK7 leads to the progression of different cancers and associated malignancies. It is becoming the next wave of targets for the development of selective and potent anti-cancerous agents. The current study is the first comprehensive computational approach to identify potent inhibitors of NEK7 protein. For this purpose, previously identified anti-inflammatory compound i.e., Phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives by our own group were selected for their anti-cancer potential via detailed Computational studies. Initially, the density functional theory (DFT) calculations were carried out using Gaussian 09 software which provided information about the compounds' stability and reactivity. Furthermore, Autodock suite and Molecular Operating Environment (MOE) software's were used to dock the ligand database into the active pocket of the NEK7 protein. Both software performances were compared in terms of sampling power and scoring power. During the analysis, Autodock results were found to be more reproducible, implying that this software outperforms the MOE. The majority of the compounds, including M7, and M12 showed excellent binding energies and formed stable protein-ligand complexes with docking scores of - 29.66 kJ/mol and - 31.38 kJ/mol, respectively. The results were validated by molecular dynamics simulation studies where the stability and conformational transformation of the best protein-ligand complex were justified on the basis of RMSD and RMSF trajectory analysis. The drug likeness properties and toxicity profile of all compounds were determined by ADMETlab 2.0. Furthermore, the anticancer potential of the potent compounds were confirmed by cell viability (MTT) assay. This study suggested that selected compounds can be further investigated at molecular level and evaluated for cancer treatment and associated malignancies.

Dataset Information

Identification of potent Yes1 kinase inhibitors using a library screening approach.

Publications

Identification of potent Yes1 kinase inhibitors using a library screening approach.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets