Dataset Information

Identification of Small Molecule Inhibitors of a Mir155 Transcriptional Reporter in Th17 Cells.

ABSTRACT: MicroRNA miR-155 is an important regulatory molecule in the immune system and is highly expressed and functional in Th17 cells, a subset of CD4⁺ T helper cells which are key players in autoimmune diseases. Small molecules that can modulate miR-155 may potentially provide new therapeutic avenues to inhibit Th17 cell-mediated autoimmune diseases. Here, we present a novel high-throughput screening assay using primary T cells from genetically engineered Mir155 reporter mice, and its use to screen libraries of small molecules to identify novel modulators of Th17 cell function. We have discovered a chemical series of (E)-1-(phenylsulfonyl)-2-styryl-1H-benzo[d] imidazoles as novel down-regulators of Mir155 reporter and cytokine expression in Th17 cells. In addition, we found that FDA approved antiparasitic agents belonging to the 'azole' family also down-regulate Mir155 reporter and cytokine expression in Th17 cells, and thus could potentially be repurposed to treat Th17-driven immunopathologies.

SUBMITTER: Singh A

PROVIDER: S-EPMC8169650 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Identification of Small Molecule Inhibitors of a Mir155 Transcriptional Reporter in Th17 Cells.

Singh Anju A Dashynam Myagmarjav M Chim Bryan B Escobar Thelma M TM Liu Xiuhuai X Hu Xin X Patnaik Samarjit S Xu Xin X Southall Noel N Marugan Juan J Jadhav Ajit A Lazarevic Vanja V Muljo Stefan A SA Ferrer Marc M

Scientific reports 20210601 1

MicroRNA miR-155 is an important regulatory molecule in the immune system and is highly expressed and functional in Th17 cells, a subset of CD4<sup>+</sup> T helper cells which are key players in autoimmune diseases. Small molecules that can modulate miR-155 may potentially provide new therapeutic avenues to inhibit Th17 cell-mediated autoimmune diseases. Here, we present a novel high-throughput screening assay using primary T cells from genetically engineered Mir155 reporter mice, and its use t ...[more]

PMID: 34075120

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Project description:Most normal cells have two centrosomes that form bipolar spindles during mitosis, while cancer cells often contain more than two, or "supernumerary" centrosomes. Such cancer cells achieve bipolar division by clustering their centrosomes into two functional poles, and inhibiting this process then leads to cancer-specific cell death. A major problem with clinically used anti-mitotic drugs, such as paclitaxel, is their toxicity in normal cells. To discover new compounds with greater specificity for cancer cells, we established a high-content screen for agents that block centrosome clustering in BT-549 cells, a breast cancer cell line that harbors supernumerary centrosomes. Using this screen, we identified 14 compounds that inhibit centrosome clustering and induce mitotic arrest. Some of these compounds were structurally similar, suggesting a common structural motif important for preventing centrosome clustering. We next compared the effects of these compounds on the growth of several breast and other cancer cell lines, an immortalized normal human mammary epithelial cell line, and progenitor-enriched primary normal human mammary epithelial cells. From these comparisons, we found some compounds that kill breast cancer cells, but not their normal epithelial counterparts, suggesting their potential for targeted therapy. One of these compounds, N2-(3-pyridylmethyl)-5-nitro-2-furamide (Centrosome Clustering Chemical Inhibitor-01, CCCI-01), that showed the greatest differential response in this screen was confirmed to have selective effects on cancer as compared to normal breast progenitors using more precise apoptosis induction and clonogenic growth endpoints. The concentration of CCCI-01 that killed cancer cells in the clonogenic assay spared normal human bone marrow hematopoietic progenitors in the colony-forming cell assay, indicating a potential therapeutic window for CCCI-01, whose selectivity might be further improved by optimizing the compound. Immunofluorescence analysis showed that treatment with CCCI-01 lead to multipolar spindles in BT-549, while maintaining bipolar spindles in the normal primary human mammary epithelial cells. Since centrosome clustering is a complex process involving multiple pathways, the 14 compounds identified in this study provide a potentially novel means to developing non-cross-resistant anti-cancer drugs that block centrosome clustering.

Dataset Information

Identification of Small Molecule Inhibitors of a Mir155 Transcriptional Reporter in Th17 Cells.

Publications

Identification of Small Molecule Inhibitors of a Mir155 Transcriptional Reporter in Th17 Cells.

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