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Integrated computational analysis identifies therapeutic targets with dual action in cancer cells and T cells

ABSTRACT: Integrated computational analysis identifies therapeutic targets with dual action in cancer cells and T cells

PROVIDER: PRJNA1089567 | ENA |

REPOSITORIES: ENA

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Integrated computational analysis identifies therapeutic targets with dual action in cancer cells and T cells

Project description:Many cancer drugs that target cancer cell pathways have detrimental effects on the immune system. We developed a computational platform for the identification of therapeutic targets with beneficial effects in both cancer and immune cells. ICRAFT (https://icraft.pku-genomics.org/) enables integrated analysis of immune-related CRISPR screen datasets, scRNA-Seq data, and pre-treatment RNA-Seq data from clinical trials. This platform enabled the discovery of a substantial number of targets with dual action in cancer cells and T cells. Among these, TNFAIP3, a ubiquitin-editing enzyme also known as A20, emerged as a leading target. Inactivating TNFAIP3 in cancer cells sensitizes them to immune attacks by activating the NF-κB pathway, while targeting it in T cells significantly enhances their antitumor efficacy.

2024-12-25 | GSE261915 | GEO

Dual-action host-guest chemistry suppresses virulence in Pseudomonas aeruginosa

Project description:Dual-action host-guest chemistry suppresses virulence in Pseudomonas aeruginosa

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Dual-action host-guest chemistry suppresses virulence in Pseudomonas aeruginosa

Project description:This study describes the influence of selected synthetic macrocycle on the gene expression in Pseudomonas aeruginosa PAO1. In this work, we propose two distinct functionalities responsible for a dual mechanism of action. We identified a water-soluble pillararene whose inner cavity tightly binds to specific homoserine lactones (HSLs) thereby interfering with interbacterial signalling, leading to effective synchronized suppression of exotoxins and biofilms in P. aeruginosa. An additional concerted mechanism of action is suggested that involves the cationic functional side groups on the pillararene that disrupt both the bacterial outer membrane and biofilms, to increase the penetration and efficacy of intracellular antibiotics.

2023-02-27 | GSE182853 | GEO

Dual-action host-guest chemistry suppresses PAO1 virulence in A549 cell line model

Project description:Dual-action host-guest chemistry suppresses PAO1 virulence in A549 cell line model

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Computational Genomics of Preeclampsia

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Computational Genomics of Preeclampsia

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A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action.

Project description:The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.

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Computational identification of clonal cells in single-cell CRISPR screens

Project description:Computational identification of clonal cells in single-cell CRISPR screens

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Computational map of colon polyps

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Indolin-2-one nitroimidazole antibiotics exhibit an unexpected dual mode of action

Project description:Nitroimidazoles such as metronidazole are used as anti-infective drugs against anaerobic bacteria. Upon in vivo reduction of the nitro group, reactive radicals damage DNA and proteins in the absence of oxygen. Unexpectedly, a recent study of nitroimidazoles linked to an indolin-2-one substituent revealed potent activities against aerobic bacteria. This suggests a different, yet undiscovered mode of action (MoA). To decipher this MoA, we first performed whole proteome analysis of compound treated cells, revealing an upregulation of bacteriophage-associated proteins, indicative of DNA damage. Since DNA binding of the compound was not observed, we applied activity-based protein profiling (ABPP) for direct target discovery. Labeling studies revealed topoisomerase IV, an essential enzyme for DNA replication, as the most enriched hit in pathogenic Staphylococcus aureus cells. Subsequent topoisomerase assays confirmed the inhibition of DNA decatenation in the presence of indolin-2-one nitroimidazole with an activity comparable to ciprofloxacin, a known inhibitor of this enzyme. Furthermore, we determined significantly increased redox potentials of indolin-2-one nitroimidazoles compared to classic 5-nitroimidazoles such as metronidazole, which facilitates in vivo reduction. Overall, this study unravels that indolin-2-one functionalized nitroimidazoles feature an unexpected dual MoA, which impairs resistance development. Given the clinical application of this compound class, the new mechanism could be a starting point to mitigate resistance.

2022-11-09 | PXD033128 | Pride

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