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Phenocopy: a strategy to qualify chemical compounds during hit-to-lead and/or lead optimization

A phenocopy is defined as an environmentally induced phenotype of one individual which is identical to the genotype-determined phenotype of another individual. The phenocopy phenomenon has been translated to the drug discovery process as phenotypes produced by the treatment of biological systems wit...

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Main Authors: Baum, Patrick (Author) , Schmid, Ramona (Author) , Ittrich, Carina (Author) , Rust, Werner (Author) , Fundel-Clemens, Katrin (Author) , Siewert, Susanne (Author) , Baur, Martin (Author) , Mara, Lisa (Author) , Gruenbaum, Lore (Author) , Heckel, Armin (Author) , Eils, Roland (Author) , Kontermann, Roland (Author) , Roth, Gerald J. (Author) , Gantner, Florian (Author) , Schnapp, Andreas (Author) , Park, John E. (Author) , Weith, Andreas (Author) , Quast, Karsten (Author) , Mennerich, Detlev (Author)
Format: Article (Journal)
Language:English
Published: December 10, 2010
In: PLOS ONE
Year: 2010, Volume: 5, Issue: 12, Pages: 1-15
ISSN:1932-6203
Online Access: Get full text
Author Notes:Patrick Baum, Ramona Schmid, Carina Ittrich, Werner Rust, Katrin Fundel-Clemens, Susanne Siewert, Martin Baur, Lisa Mara, Lore Gruenbaum, Armin Heckel, Roland Eils, Roland E. Kontermann, Gerald J. Roth, Florian Gantner, Andreas Schnapp, John E. Park, Andreas Weith, Karsten Quast, Detlev Mennerich
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Summary:A phenocopy is defined as an environmentally induced phenotype of one individual which is identical to the genotype-determined phenotype of another individual. The phenocopy phenomenon has been translated to the drug discovery process as phenotypes produced by the treatment of biological systems with new chemical entities (NCE) may resemble environmentally induced phenotypic modifications. Various new chemical entities exerting inhibition of the kinase activity of Transforming Growth Factor β Receptor I (TGF-βR1) were qualified by high-throughput RNA expression profiling. This chemical genomics approach resulted in a precise time-dependent insight to the TGF-β biology and allowed furthermore a comprehensive analysis of each NCE's off-target effects. The evaluation of off-target effects by the phenocopy approach allows a more accurate and integrated view on optimized compounds, supplementing classical biological evaluation parameters such as potency and selectivity. It has therefore the potential to become a novel method for ranking compounds during various drug discovery phases.
Item Description:Gesehen am 15.12.2022
Physical Description:Online Resource
ISSN:1932-6203

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