Evidence for a molecular mechanism of teratogenicity of SB‐236057, a 5‐HT1B receptor inverse agonist that alters axial formation

Augustine-Rauch, Karen; Zhang, Qin J.; Leonard, Jennifer L.; Chadderton, Antony; Welsh, Michael J.; Rami, Harshad K.; Thompson, Mervyn; Gaster, Laramie M.; Wier, Patrick J.

doi:10.1002/bdra.20076

Cited by 7 publications

(7 citation statements)

References 40 publications

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“…Other compounds found in this cluster, such as haloperidol and reserpine, were not specifically associated with activation of the estrogen receptor pathway. Another compound, the teratogen cyclopamine, acts through the sonic hedgehog pathway to downregulate estrogen receptor-α protein, and DPharma34, also known as SB-236057, has teratogenic effects through pathways similar to those of cyclopamine 28 . Inspection of the compound profiles in cluster 48 and comparison with estrogen receptor agonists (cluster 28) revealed tissue factor (TF) in the 3C system as a discriminating activity of particular interest (Fig.…”

Section: Chemical Clusteringmentioning

confidence: 99%

Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms

et al. 2014

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Addressing the safety aspects of drugs and environmental chemicals has historically been undertaken through animal testing. However, the quantity of chemicals in need of assessment and the challenges of species extrapolation require the development of alternative approaches. Our approach, the US Environmental Protection Agency's ToxCast program, utilizes a large suite of in vitro and model organism assays to interrogate important chemical libraries and computationally analyze bioactivity profiles. Here we evaluated one component of the ToxCast program, the use of primary human cell systems, by screening for chemicals that disrupt physiologically important pathways. Chemical-response signatures for 87 endpoints covering molecular functions relevant to toxic and therapeutic pathways were generated in eight cell systems for 641 environmental chemicals and 135 reference pharmaceuticals and failed drugs. Computational clustering of the profiling data provided insights into the polypharmacology and potential off-target effects for many chemicals that have limited or no toxicity information. The endpoints measured can be closely linked to in vivo outcomes, such as the upregulation of tissue factor in endothelial cell systems by compounds linked to the risk of thrombosis in vivo. Our results demonstrate that assaying complex biological pathways in primary human cells can identify potential chemical targets, toxicological liabilities and mechanisms useful for elucidating adverse outcome pathways.

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Section: Chemical Clusteringmentioning

confidence: 99%

Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms

et al. 2014

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“…The heptapeptide was further identified in screenings with a teratogenic serotonin receptor inverse agonist (SB-236057) [ 108 ], different rRNA targets [ 109 ] and the following protein targets: monoclonal anti-angiogenic antibody [ 110 ], melanoma inhibitory activity (MIA) protein [ 111 ], prion protein [ 112 ], chromatin high mobility group protein 1 [ 23 ] and an epitope on kidney-specific H-ATPase subunit G3 [ 113 ]. Although the binding of the LPLTPLP peptide to SB-236057, monoclonal anti-angiogenic antibody and MIA was not or could not be demonstrated [ 108 , 110 , 111 ], its affinity towards rRNA, prion protein and HMGB1 was confirmed by on-bead fluorescence assay, ELISA and Far-Western blotting, respectively [ 23 , 109 , 112 ]. Various authors have identified different proteins that contain regions with a high degree of homology to the selected LPLTPLP [ 108 , 112 , 113 ].…”

Section: Frequently Isolated Peptides/motifs Of Unknown Specificitmentioning

confidence: 99%

Phage Display: Selecting Straws Instead of a Needle from a Haystack

et al. 2011

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An increasing number of peptides with specific binding affinity to various protein and even non-protein targets are being discovered from phage display libraries. The power of this method lies in its ability to efficiently and rapidly identify ligands with a desired target property from a large population of phage clones displaying diverse surface peptides. However, the search for the needle in the haystack does not always end successfully. False positive results may appear. Thus instead of specific binders phage with no actual affinity toward the target are recovered due to their propagation advantages or binding to other components of the screening system, such as the solid phase, capturing reagents, contaminants in the target sample or blocking agents, rather than the target. Biopanning experiments on different targets performed in our laboratory revealed some previously identified and many new target-unrelated peptide sequences, which have already been frequently described and published, but not yet recognized as target-unrelated. Distinguishing true binders from false positives is an important step toward phage display selections of greater integrity. This article thoroughly reviews and discusses already identified and new target-unrelated peptides and suggests strategies to avoid their isolation.

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“…For instance, the DMS system has been used to assess embryonic delivery efficiency of compounds formulated in various vehicles (Augustine‐Rauch, Zhang et al, 2004a). In a similar application, it has also been used to determine by phenotype (in comparison to knockout morphology), relative specificity and potency of targeted gene expression inhibition by antisense oligonucleotide treatment (Augustine‐Rauch, Zhang et al, 2004b).…”

Section: Discussionmentioning

confidence: 99%

“…In most cases, the standard test concentrations ranged from 0.1 to 100 µM, although there were some exceptions depending upon the study design and potency of the compound in producing general toxicity. Typical vehicles included 0.02–0.04% Tyrodes buffer (depending on the solubility of test compounds), 0.02% aged DMSO or 0.02% DMF (Augustine‐Rauch, Zhang et al, 2004a, b).…”

Section: Methodsmentioning

confidence: 99%

A dysmorphology score system for assessing embryo abnormalities in rat whole embryo culture

Zhang

Danberry

Jacobs

et al. 2010

Birth Defects Research Pt B

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Evidence for a molecular mechanism of teratogenicity of SB‐236057, a 5‐HT1B receptor inverse agonist that alters axial formation

Cited by 7 publications

References 40 publications

Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms

Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms

Phage Display: Selecting Straws Instead of a Needle from a Haystack

A dysmorphology score system for assessing embryo abnormalities in rat whole embryo culture

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