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Effect of SMNDC1 small molecule inhibition on gene expression

ABSTRACT: Effect of SMNDC1 small molecule inhibition on gene expression

PROVIDER: PRJNA966990 | ENA |

REPOSITORIES: ENA

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Effect of SMNDC1 small molecule inhibition on gene expression

Project description:To investigate the effect of treating alphaTC1 cells with a small molecule inhibitor against SMNDC1, we treated cells with DMSO (control) or compound (G786-1089) for 16h. We then performed gene expression profiling analysis and splicing analysis using data obtained from RNA-seq.

2023-07-20 | GSE231600 | GEO

Pharmacological perturbation of the phase-separating protein SMNDC1

Project description:SMNDC1 is an essential splicing factor that, like its better-studied paralog SMN, binds to di-methylated arginines using its Tudor domain. The specific contributions of the SMNDC1 Tudor domain to protein-protein interactions, subcellular localization, and molecular function have not been studied in detail. Here, we perform such analysis and develop first small molecule inhibitors targeting the dimethyl arginine binding pocket of the SMNDC1 Tudor domain. We find that SMNDC1 localizes to phase-separated membraneless organelles that partially overlap with nuclear speckles. This condensation behavior is driven by the unstructured C-terminus, dependent on RNA interaction and can be recapitulated in vitro. Inhibitors of the protein’s Tudor domain drastically alter protein-protein interactions and subcellular localization, causing splicing changes at SMNDC1 dependent genes. These compounds will enable further pharmacological studies on the role of SMNDC1 in the regulation of nuclear condensates, gene regulation and cell identity.

2023-09-04 | PXD037092 | Pride

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Small-molecule Inhibition of METTL3 Suppresses Tumor Growth and Promotes Neuroblastoma Differentiation

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Molecular basis of USP7 inhibition by selective small molecule inhibitors

Project description:Modification by ubiquitin controls the stability of most cellular proteins, and deregulation contributes to a variety of human diseases such as cancer. Deubiquitinases (DUBs) remove ubiquitin from proteins, and the inhibition of DUBs has been recognized as a therapeutic strategy to induce degradation of specific proteins, a concept extendable to ‘undruggable’ targets such as transcription factors. However, this potential has remained untapped; specific small molecule inhibitors for DUBs are scarce and insights into mechanisms of action are limited. Ubiquitin specific protease (USP) 7 stabilises the oncogenic E3 ligase MDM2 that destabilises the tumour suppressor p53 and inhibition of USP7 results in MDM2 degradation and p53 re-activation in a variety of cancers. We here present two small molecule inhibitors, FT671 and FT827, that inhibit USP7 with nanomolar affinity and display exquisite specificity towards USP7 in vitro and in cells. USP7-inhibitor co-crystal structures reveal that both compounds target the auto-inhibited apo-form of USP7 and bind in proximity to the misaligned catalytic triad in a dynamic hydrophobic pocket that serves as the binding site for the ubiquitin C-terminus. The unique auto-inhibited conformation of apo USP7 differs from other USP DUBs, explaining compound selectivity. Consistent with USP7 target engagement in cells, FT671 destabilises MDM2, stabilises p53 and results in transcription of p53 target genes, induction of the tumour suppressor p21, and tumour growth inhibition in vivo.

2018-04-05 | PXD006418 | Pride

Impact of small molecule and genetic inhibition of PKM2 in muscle progenitor cells

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Small molecule inhibition of multiple RNA binding proteins underlies Musashi-2 independent phenotypes

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Identification of resistance mechanisms to small-molecule inhibition of YAP/TEAD-regulated transcription

Project description:Identification of resistance mechanisms to small-molecule inhibition of YAP/TEAD-regulated transcription

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Identification of resistance mechanisms to small-molecule inhibition of YAP/TEAD-regulated transcription [RNA-seq]

Project description:The Hippo tumour suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some now entering clinical trials for different cancers. Here, we investigated the cellular response to TEAD palmitoylation inhibitors, using genomic and genetic strategies. Genome-wide CRISPR/Cas9 screens revealed that mutations in genes from the Hippo, MAPK and JAK-STAT signaling pathways all modulate the cellular response to TEAD inhibition. Inhibition of TEAD palmitoylation strongly reduced YAP/TEAD target expression, whilst only mildly impacting YAP/TEAD genome binding. Additionally, expression of MAPK pathway genes was induced upon inhibition of TEAD palmitoylation, which coincided with YAP/TEAD redistribution to AP-1 transcription factor binding sites. Consistent with this, combined inhibition of TEAD and the MAPK protein MEK, synergistically blocked proliferation of several mesothelioma and lung cancer cell lines and more potently reduced the growth of patient-derived lung cancers in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.

2024-07-08 | GSE269899 | GEO

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