title: Phenocopy--a strategy to qualify chemical compounds during hit-to-lead and/or lead optimization.
abstract: 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.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Baum
authors.forename: Ramona
authors.initials: R
authors.lastname: Schmid
authors.forename: Carina
authors.initials: C
authors.lastname: Ittrich
authors.forename: Werner
authors.initials: W
authors.lastname: Rust
authors.forename: Katrin
authors.initials: K
authors.lastname: Fundel-Clemens
authors.forename: Susanne
authors.initials: S
authors.lastname: Siewert
authors.forename: Martin
authors.initials: M
authors.lastname: Baur
authors.forename: Lisa
authors.initials: L
authors.lastname: Mara
authors.forename: Lore
authors.initials: L
authors.lastname: Gruenbaum
authors.forename: Armin
authors.initials: A
authors.lastname: Heckel
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kontermann
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Roth
authors.forename: Florian
authors.initials: F
authors.lastname: Gantner
authors.forename: Andreas
authors.initials: A
authors.lastname: Schnapp
authors.forename: John E
authors.initials: JE
authors.lastname: Park
authors.forename: Andreas
authors.initials: A
authors.lastname: Weith
authors.forename: Karsten
authors.initials: K
authors.lastname: Quast
authors.forename: Detlev
authors.initials: D
authors.lastname: Mennerich
mesh_terms: D045744:Cell Line, Tumor; D015195:Drug Design; D055808:Drug Discovery; D004345:Drug Industry / Q000379:methods; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023281:Genomics; D006801:Humans; D008956:Models, Chemical; D009693:Nucleic Acid Hybridization; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D012313:RNA; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I