Browsing by Author "Baum, Patrick"

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Open Access
Phenocopy : a strategy to qualify chemical compounds during hit-to-lead and/or lead optimization
(2010) Baum, Patrick; Kontermann, Roland (Prof. Dr.)
A phenocopy is defined as an environmentally induced phenotype of one individual which is identical to the genotype determined phenotype of another individual. In the present work, the phenocopy phenomenon has been translated to the drug discovery process as phenotypes produced by the treatment of cellular systems with small interfering RNAs (siRNAs) or new chemical entities (NCE) may resemble environmentally induced phenotypic modifications. Various new chemical entities exerting inhibition of the kinase activity of Transforming Growth Factor Beta Receptor I (TGF-betaR1) were ranked by high-throughput RNA expression profiling. This chemical genomics approach was able to unravel both on-target effects (effects, caused by the inhibition of the drug target) and off-target effects (effects, caused by the interaction of the NCE with additional molecules). It resulted in a precise time-dependent insight into the TGF-beta biology (referred to as on-target signature) and allowed furthermore a comprehensive analysis of each NCE's off-target effects (re-ferred to as off-target signatures). Both signature types can support the drug discovery process. The on-target signature helps to characterize the mode of action of the drug target (TGF-betaR1) and thereby supports the target validation as well as the assay development process. Furthermore, the evaluation of off-target effects by the Phenocopy approach allows a more accurate and integrated view on the mode of action of the compounds, supplementing classical biological evaluation parameters such as potency and selectivity. The presented proof of concept study allowed the ranking of NCEs that were before indistinguishable solely based on potency and selectivity. According to the newly introduced criteria, several of the tested NCEs revealed liabilities at e.g. the induction of off-target effects and of induction of gene regulation inverse to the desired TGF-beta inhibition effect, at the induction of cell death, at acting as pro-inflammatory stimuli and as promoting cellular growth and at induction of cancer pathways. Ultimately, this approach has therefore the potential to become a novel method for ranking compounds during various drug discovery phases.