scholarly journals Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers

Oncotarget ◽  
2017 ◽  
Vol 8 (25) ◽  
pp. 39963-39977 ◽  
Author(s):  
Lakshmi Prabhu ◽  
Han Wei ◽  
Lan Chen ◽  
Özlem Demir ◽  
George Sandusky ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
Small Molecule Inhibitor ◽  
Colorectal Cancers ◽  
High Throughput Screen ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Molecule Inhibitor ◽  
Protein Arginine Methyltransferase 5

scholarly journals Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sara Busacca ◽  
Qi Zhang ◽  
Annabel Sharkey ◽  
Alan G. Dawson ◽  
David A. Moore ◽  
...  
Keyword(s):  
Small Molecule ◽  
Selective Vulnerability ◽  
Dependent Manner ◽  
Histone H4 ◽  
Wild Type ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Methylthioadenosine Phosphorylase ◽  
Protein Arginine Methyltransferase 5

AbstractWe hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

scholarly journals A Novel Dengue Virus Inhibitor, BP13944, Discovered by High-Throughput Screening with Dengue Virus Replicon Cells Selects for Resistance in the Viral NS2B/NS3 Protease

2013 ◽  
Vol 58 (1) ◽  
pp. 110-119 ◽  
Author(s):  
Chi-Chen Yang ◽  
Han-Shu Hu ◽  
Ren-Huang Wu ◽  
Szu-Huei Wu ◽  
Shiow-Ju Lee ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Small Molecule Inhibitor ◽  
Current Treatment ◽  
Stable Cell Line ◽  
Epidemic Disease ◽  
Molecule Inhibitor ◽  
Ns3 Protease

ABSTRACTDengue virus (DENV) causes disease globally, resulting in an estimated 25 to 100 million new infections per year. No effective DENV vaccine is available, and the current treatment is only supportive. Thus, there is an urgent need to develop therapeutic agents to cure this epidemic disease. In the present study, we identified a potential small-molecule inhibitor, BP13944, via high-throughput screening (HTS) of 60,000 compounds using a stable cell line harboring an efficient luciferase replicon of DENV serotype 2 (DENV-2). BP13944 reduced the expression of the DENV replicon reporter in cells, showing a 50% effective concentration (EC50) of 1.03 ± 0.09 μM. Without detectable cytotoxicity, the compound inhibited replication or viral RNA synthesis in all four serotypes of DENV but not in Japanese encephalitis virus (JEV). Sequencing analyses of several individual clones derived from BP13944-resistant RNAs purified from cells harboring the DENV-2 replicon revealed a consensus amino acid substitution (E66G) in the region of the NS3 protease domain. Introduction of E66G into the DENV replicon, an infectious DENV cDNA clone, and recombinant NS2B/NS3 protease constructs conferred 15.2-, 17.2-, and 3.1-fold resistance to BP13944, respectively. Our results identify an effective small-molecule inhibitor, BP13944, which likely targets the DENV NS3 protease. BP13944 could be considered part of a more effective treatment regime for inhibiting DENV in the future.

scholarly journals High-Throughput Screening Reveals a Small-Molecule Inhibitor of the Renal Outer Medullary Potassium Channel and Kir7.1

2009 ◽  
Vol 76 (5) ◽  
pp. 1094-1103 ◽  
Author(s):  
L. Michelle Lewis ◽  
Gautam Bhave ◽  
Brian A. Chauder ◽  
Sreedatta Banerjee ◽  
Katharina A. Lornsen ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Protein arginine methyltransferase 5 promotes metastasis via enhancing EGFR transcription and modulating AKT1 activation by methylation

2020 ◽  
Author(s):  
Lei Huang ◽  
Xiao-Ou Zhang ◽  
Odette Verdejo-Torres ◽  
Kim Wigglesworth ◽  
Xiaomei Sun ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Metastatic Cancer ◽  
Growth Factor Receptor ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Mesenchymal Transition ◽  
Molecule Inhibitor ◽  
Wide Range ◽  
Protein Arginine Methyltransferase 5

AbstractProtein arginine methyltransferase 5 (PRMT5) regulates a wide range of physiological processes, including cancer cell proliferation and metastasis, by generating symmetric di-methyl-arginine marks on histones and non-histone proteins. Here, we report that PRMT5 directly regulates epidermal growth factor receptor (EGFR) transcription to control EGF stimulated EGFR signaling. Furthermore, PRMT5 modulates protein kinase B (AKT) activation by methylation of AKT1 Arg 15, which is required for its subsequent phosphorylation at AKT1 Thr 308 and Ser 473. The PRMT5/EGFR/AKT axis converges to regulate transcription factors ZEB1, SNAIL, and TWIST1 to promote the epithelial-mesenchymal transition (EMT), in the manner that EGFR and AKT1 compensate each other to support tumor cell invasion and metastasis. Inhibiting PRMT5 methyltransferase activity with a small molecule inhibitor attenuated primary tumor growth and prevented hepatic metastasis in aggressive in vivo tumor models. Collectively, our results support the use of PRMT5 based therapies for metastatic cancer.

Necrosulfonamide inhibits necroptosis by selectively targeting the mixed lineage kinase domain-like protein

MedChemComm ◽  
2014 ◽  
Vol 5 (3) ◽  
pp. 333-337 ◽  
Author(s):  
Daohong Liao ◽  
Liming Sun ◽  
Weilong Liu ◽  
Sudan He ◽  
Xiaodong Wang ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Kinase Domain ◽  
Small Molecule Inhibitor ◽  
Mixed Lineage Kinase ◽  
Sar Studies ◽  
Structure Activity ◽  
Molecule Inhibitor ◽  
Smac Mimetic

Through high-throughput screening of 200 000 compounds and subsequent structure–activity relationship (SAR) studies we identified necrosulfonamide (NSA) as a potent small molecule inhibitor for necroptosis, induced by a combination of TNF-a, Smac mimetic, and z-VAD-fmk (T/S/Z).

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