Similar Datasets
Project description:Chimeric antigen receptor T cells (CAR-Ts) with T-stem cell (TSCM)-like phenotypic characteristics promote sustained antitumor effects. We performed an unbiased and automated high-throughput screen of a kinase-focused compound set to identify kinase inhibitors (KIs) that preserve human TSCM-like CAR-Ts. We identified three KIs UNC10225387B, UNC10225263A and UNC10112761A that combined in vitro increased the frequency of CD45RA+CCR7+TCF1high TSCM-like CAR-Ts from both healthy donors and cancer patients. KIs-treated CAR-Ts showed enhanced antitumor effects both in vitro and in vivo. The KI cocktail maintains TSCM-like phenotype preferentially in CAR-Ts originating from naïve T cells, and promotes dynamic transcriptomic changes without arresting T-cell activation or modulating the chromatin organization. Specific kinases ITK, ADCK3, MAP3K4 and CDK13 targeted by the KI cocktail in a dose-dependent manner are directly associated with the preservation of TSCM-like CAR-Ts. While individual knockdown of these kinases or their combination enriched in TSCM-like CAR-Ts, only CAR-Ts generated in the presence of the KI cocktail show robust expansion and differentiation upon stimulation with tumor cells. Overall, transient pharmacologic inhibition of strategically targeted kinases maintains stem-like features of CAR-Ts and improves their antitumor activity.
2025-01-20 | GSE261127 | GEO
Project description:Chimeric antigen receptor T cells (CAR-Ts) with T-stem cell (TSCM)-like phenotypic characteristics promote sustained antitumor effects. We performed an unbiased and automated high-throughput screen of a kinase-focused compound set to identify kinase inhibitors (KIs) that preserve human TSCM-like CAR-Ts. We identified three KIs UNC10225387B, UNC10225263A and UNC10112761A that combined in vitro increased the frequency of CD45RA+CCR7+TCF1high TSCM-like CAR-Ts from both healthy donors and cancer patients. KIs-treated CAR-Ts showed enhanced antitumor effects both in vitro and in vivo. The KI cocktail maintains TSCM-like phenotype preferentially in CAR-Ts originating from naïve T cells, and promotes dynamic transcriptomic changes without arresting T-cell activation or modulating the chromatin organization. Specific kinases ITK, ADCK3, MAP3K4 and CDK13 targeted by the KI cocktail in a dose-dependent manner are directly associated with the preservation of TSCM-like CAR-Ts. While individual knockdown of these kinases or their combination enriched in TSCM-like CAR-Ts, only CAR-Ts generated in the presence of the KI cocktail show robust expansion and differentiation upon stimulation with tumor cells. Overall, transient pharmacologic inhibition of strategically targeted kinases maintains stem-like features of CAR-Ts and improves their antitumor activity.
2025-01-20 | GSE261109 | GEO
Project description:A Multi-Kinase Inhibitor Screen Identifies Inhibitors Preserving Stem-Cell-Like Chimeric Antigen Receptor T Cells
| PRJNA1085332 | ENA
Project description:A Multi-Kinase Inhibitor Screen Identifies Inhibitors Preserving Stem-Cell-Like Chimeric Antigen Receptor T Cells [RNA-Seq]
| PRJNA1085492 | ENA
Project description:A Multi-Kinase Inhibitor Screen Identifies Inhibitors Preserving Stem-Cell-Like Chimeric Antigen Receptor T Cells [ATAC-Seq]
| PRJNA1085330 | ENA
Project description:An epithelial to mesenchymal transition (EMT) enables epithelial tumor cells to break out of the primary tumor mass and to metastasize. Understanding the molecular mechanisms driving EMT in more detail will provide important tools to interfere with the metastatic process. To identify pharmacological modulators and druggable targets of EMT, we have established a novel multi-parameter, high-content, microscopy-based assay and screened chemical compounds with activities against known targets. Out of 3423 compounds, we have identified 19 drugs that block transforming growth factor beta (TGFβ)-induced EMT in normal murine mammary gland epithelial cells (NMuMG). The active compounds include inhibitors against TGFβ receptors (TGFBR), Rho-associated protein kinases (ROCK), myosin II, SRC kinase and uridine analogues. Among the EMT-repressing compounds, we identified a group of inhibitors targeting multiple receptor tyrosine kinases, and biochemical profiling of these multi-kinase inhibitors reveals TGFBR as a thus far unknown target of their inhibitory spectrum. These findings demonstrate the feasibility of a multi-parameter, high-content microscopy screen to identify modulators and druggable targets of EMT. Moreover, the newly discovered "off-target" effects of several receptor tyrosine kinase inhibitors have important consequences for in vitro and in vivo studies and might beneficially contribute to the therapeutic effects observed in vivo.
| S-EPMC5041959 | biostudies-literature
Project description:The non-receptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) is a critical mediator of signaling from cell surface growth factor and adhesion receptors to cell migration, proliferation, and survival. Emerging evidence indicates that signaling by Pyk2 regulates hematopoietic cell response, bone density, neuronal degeneration, angiogenesis, and cancer. These physiological and pathological roles of Pyk2 warrant it as a valuable therapeutic target for invasive cancers, osteoporosis, Alzheimer's disease, and inflammatory cellular response. Despite its potential as a therapeutic target, no potent and selective inhibitor of Pyk2 is available at present. As a first step toward discovering specific potential inhibitors of Pyk2, we used an in silico high-throughput screening approach. A virtual library of six million lead-like compounds was docked against four different high-resolution Pyk2 kinase domain crystal structures and further selected for predicted potency and ligand efficiency. Ligand selectivity for Pyk2 over focal adhesion kinase (FAK) was evaluated by comparative docking of ligands and measurement of binding free energy so as to obtain 40 potential candidates. Finally, the structural flexibility of a subset of the docking complexes was evaluated by molecular dynamics simulation, followed by intermolecular interaction analysis. These compounds may be considered as promising leads for further development of highly selective Pyk2 inhibitors.
| S-EPMC5441678 | biostudies-literature
Project description: Not available
| S-EPMC7433347 | biostudies-literature
Project description:Bacterial signaling systems such as protein kinases and quorum sensing have become increasingly attractive targets for the development of novel antimicrobial agents in a time of rising antibiotic resistance. The family of bacterial Penicillin-binding-protein And Serine/Threonine kinase-Associated (PASTA) kinases is of particular interest due to the role of these kinases in regulating resistance to ?-lactam antibiotics. As such, small-molecule kinase inhibitors that target PASTA kinases may prove beneficial as treatments adjunctive to ?-lactam therapy. Despite this interest, only limited progress has been made in identifying functional inhibitors of the PASTA kinases that have both activity against the intact microbe and high kinase specificity. Here, we report the results of a small-molecule screen that identified GSK690693, an imidazopyridine aminofurazan-type kinase inhibitor that increases the sensitivity of the intracellular pathogen Listeria monocytogenes to various ?-lactams by inhibiting the PASTA kinase PrkA. GSK690693 potently inhibited PrkA kinase activity biochemically and exhibited significant selectivity for PrkA relative to the Staphylococcus aureus PASTA kinase Stk1. Furthermore, other imidazopyridine aminofurazans could effectively inhibit PrkA and potentiate ?-lactam antibiotic activity to varying degrees. The presence of the 2-methyl-3-butyn-2-ol (alkynol) moiety was important for both biochemical and antimicrobial activity. Finally, mutagenesis studies demonstrated residues in the back pocket of the active site are important for GSK690693 selectivity. These data suggest that targeted screens can successfully identify PASTA kinase inhibitors with both biochemical and antimicrobial specificity. Moreover, the imidazopyridine aminofurazans represent a family of PASTA kinase inhibitors that have the potential to be optimized for selective PASTA kinase inhibition.
| S-EPMC5641865 | biostudies-literature
Project description:Otitis media, the most common disease of childhood, is characterized by extensive changes in the morphology of the middle ear cavity. This includes hyperplasia of the mucosa that lines the tympanic cavity, from a simple monolayer of squamous epithelium into a greatly thickened, respiratory-type mucosa. The processes that control this response, which is critical to otitis media pathogenesis and recovery, are incompletely understood. Given the central role of protein phosphorylation in most intracellular processes, including cell proliferation and differentiation, we screened a library of kinase inhibitors targeting members of all the major families in the kinome for their ability to influence the growth of middle ear mucosal explants in vitro. Of the 160 inhibitors, 30 were found to inhibit mucosal growth, while two inhibitors enhanced tissue proliferation. The results suggest that the regulation of infection-mediated tissue growth in the ME mucosa involves multiple cellular processes that span the kinome. While some of the pathways and processes identified have been previously implicated in mucosa hyperplasia others are novel. The results were used to generate a global model of growth regulation by kinase pathways. The potential for therapeutic applications of the results are discussed.
| S-EPMC7410257 | biostudies-literature