scholarly journals Discovery of PqsE Thioesterase Inhibitors for Pseudomonas aeruginosa Using DNA-Encoded Small Molecule Library Screening

2019 ◽  
Vol 15 (2) ◽  
pp. 446-456 ◽  
Author(s):  
Julie S. Valastyan ◽  
Michael R. Tota ◽  
Isabelle R. Taylor ◽  
Vasiliki Stergioula ◽  
Graham A. B. Hone ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Small Molecule ◽  
Library Screening ◽  
Small Molecule Library

Modulating AML1-ETO with Signature-Based Small Molecule Library Screening.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 729-729 ◽  
Author(s):  
Kimberly Stegmaier ◽  
Steven M. Corsello ◽  
Kenneth N. Ross ◽  
Todd R. Golub
Keyword(s):  
Gene Expression ◽  
Small Molecule ◽  
Dna Methyltransferase ◽  
Chemical Diversity ◽  
Gene Set Enrichment Analysis ◽  
Cytotoxic Agents ◽  
Whole Genome ◽  
Library Screening ◽  
Acute Leukemias ◽  
Small Molecule Library

Abstract We sought to develop a strategy to pharmacologically modulate AML1-ETO, the most common gene rearrangement associated with acute myeloblastic leukemia (AML). Like many other oncogenic transcription factors associated with the acute leukemias, AML1-ETO has been considered undruggable. In principle, these well-characterized somatic mutations identified in the acute leukemias represent unique, tumor-specific therapeutic targets. In practice, acute leukemia therapy continues to focus on nonspecific cytotoxic agents. In order to address this challenge, we developed a genomic, signature-based small molecule library screening approach, Gene Expression-based High-throughput Screening (GE-HTS). This approach uses gene expression signatures as surrogates for different biological states in a small molecule library screen. We focused our initial efforts on identifying modulators of AML1-ETO. First, a 25-gene signature for AML1-ETO abrogation was defined by transcriptional profiling of t(8;21) Kasumi-1 cells with and without AML1-ETO-directed RNA interference and with a U937 inducible model of AML1-ETO. The signature was confirmed in microarray data from t(8;21)-containing primary patient leukemias (p < 0.001). Next, the ability of 2,600 FDA-approved drugs and bioactive agents to induce this abrogation signature was evaluated by ligation mediated amplification (LMA) and bead-based fluorescence detection. The screen identified 16 hits confirmed on repeat testing, including seven corticosteroids. Five hits were selected for further study based on their chemical diversity, ability to induce a robust expression signature, and potential for clinical translation: 5-aza-deoxycytidine, floxuridine, methotrexate, methylprednisolone, and pyrimethamine. Next, whole genome effects of these compounds with microarray-based expression profiling were evaluated. Using Gene Set Enrichment Analysis (GSEA), we determined that all five compounds induce both whole genome effects consistent with AML1-ETO knockdown and a whole genome program consistent with neutrophil maturation. In a subset of these compounds, we also see changes in cell surface markers and morphological features consistent with myeloid maturation. Intriguingly, two of the hits are well-characterized DNA methyltransferase inhibitors, and two of the hits are dihydrofolate reductase inhibitors that increase S-adenosylhomocysteine, an inhibitor of methyltransferases. Thus, reversal of AML1-ETO-mediated gene silencing by demethylation may overcome its repressive effects. This application of knockdown-derived expression signatures to small molecule library screening should enable the targeting of nearly any oncogenic transcription factor.

Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity

2017 ◽  
Author(s):  
Carolyn Bertozzi ◽  
Fred Tomlin ◽  
Ulla Gerling-Driessen ◽  
Yi-Chang Liu ◽  
Ryan Flynn ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Molecule ◽  
Proteasome Inhibitor ◽  
Activation Mechanism ◽  
Cancer Drugs ◽  
Small Molecule Library ◽  
Library Screen ◽  
In Cells

We discovered that the proteostasis modulating transcription factor Nrf1 requires cytosolic de-N-glycosylation by the N-glycanase NGly1 as part of its activation mechanism. Through a covalent small molecule library screen, we discovered an inhibitor of NGly1 that blocks Nrf1 activation in cells and potentiates the activity of proteasome inhibitor cancer drugs. The requirement of NGly1 for Nrf1 activity likely underlies several pathologies associated with a rare hereditary deficiency in NGly1.

scholarly journals A Rapid Phenotypic Whole-Cell Screening Approach for the Identification of Small-Molecule Inhibitors That Counter β-Lactamase Resistance in Pseudomonas aeruginosa

2017 ◽  
Vol 23 (1) ◽  
pp. 55-64 ◽  
Author(s):  
Deanna Collia ◽  
Thomas D. Bannister ◽  
Hao Tan ◽  
Shouguang Jin ◽  
Taimour Langaee ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Laboratory Strain ◽  
Multidrug Resistant ◽  
First Line ◽  
Strain Pao1 ◽  
Whole Cell ◽  
Bacterial Sensitivity ◽  
Opportunistic Human Pathogen

Pseudomonas aeruginosa is an opportunistic human pathogen that is prevalent in hospitals and continues to develop resistance to multiple classes of antibiotics. Historically, β-lactam antibiotics have been the first line of therapeutic defense. However, the emergence of multidrug-resistant (MDR) strains of P. aeruginosa, such as AmpC β-lactamase overproducing mutants, limits the effectiveness of current antibiotics. Among AmpC hyperproducing clinical isolates, inactivation of AmpG, which is essential for the expression of AmpC, increases bacterial sensitivity to β-lactam antibiotics. We hypothesize that inhibition of AmpG activity will enhance the efficacy of β-lactams against P. aeruginosa. Here, using a highly drug-resistant AmpC-inducible laboratory strain PAO1, we describe an ultra-high-throughput whole-cell turbidity assay designed to identify small-molecule inhibitors of the AmpG. We screened 645,000 compounds to identify compounds with the ability to inhibit bacterial growth in the presence of cefoxitin, an AmpC inducer, and identified 2663 inhibitors that were also tested in the absence of cefoxitin to determine AmpG specificity. The Z′ and signal-to-background ratio were robust at 0.87 ± 0.05 and 2.2 ± 0.2, respectively. Through a series of secondary and tertiary studies, including a novel luciferase-based counterscreen, we ultimately identified eight potential AmpG-specific inhibitors.

scholarly journals Evaluation of ethyl N-(2-phenethyl) carbamate analogues as biofilm inhibitors of methicillin resistant Staphylococcus aureus

2016 ◽  
Vol 14 (28) ◽  
pp. 6853-6856 ◽  
Author(s):  
Matthew D. Stephens ◽  
Nisakorn Yodsanit ◽  
Christian Melander
Keyword(s):  
Staphylococcus Aureus ◽  
Small Molecule ◽  
Broad Spectrum ◽  
Biofilm Formation ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Small Molecule Library

A small molecule library consisting of 45 compounds was synthesized based on the bacterial metabolite ethylN-(2-phenethyl) carbamate. From this library, a more potent, broad-spectrum inhibitor of MRSA biofilm formation was discovered.

scholarly journals CHI PMUNK: A Virtual Synthesizable Small-Molecule Library for Medicinal Chemistry, Exploitable for Protein-Protein Interaction Modulators

ChemMedChem ◽  
2018 ◽  
Vol 13 (6) ◽  
pp. 532-539 ◽  
Author(s):  
Lina Humbeck ◽  
Sebastian Weigang ◽  
Till Schäfer ◽  
Petra Mutzel ◽  
Oliver Koch
Keyword(s):  
Small Molecule ◽  
Protein Interaction ◽  
Medicinal Chemistry ◽  
Protein Protein Interaction ◽  
Small Molecule Library
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