title: Integrating High-Dimensional Transcriptomics and Image Analysis Tools into Early Safety Screening: Proof of Concept for a New Early Drug Development Strategy.
abstract: During drug discovery and development, the early identification of adverse effects is expected to reduce costly late-stage failures of candidate drugs. As risk/safety assessment takes place rather late during the development process and due to the limited ability of animal models to predict the human situation, modern unbiased high-dimensional biology readouts are sought, such as molecular signatures predictive for in vivo response using high-throughput cell-based assays. In this theoretical proof of concept, we provide findings of an in-depth exploration of a single chemical core structure. Via transcriptional profiling, we identified a subset of close analogues that commonly downregulate multiple tubulin genes across cellular contexts, suggesting possible spindle poison effects. Confirmation via a qualified toxicity assay (in vitro micronucleus test) and the identification of a characteristic aggregate-formation phenotype via exploratory high-content imaging validated the initial findings. SAR analysis triggered the synthesis of a new set of compounds and allowed us to extend the series showing the genotoxic effect. We demonstrate the potential to flag toxicity issues by utilizing data from exploratory experiments that are typically generated for target evaluation purposes during early drug discovery. We share our thoughts on how this approach may be incorporated into drug development strategies.
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Bie M P
authors: BM
authors: Verbist
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Geert R
authors: GR
authors: Verheyen
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Liesbet
authors: L
authors: Vervoort
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Marjolein
authors: M
authors: Crabbe
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Dominiek
authors: D
authors: Beerens
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Cindy
authors: C
authors: Bosmans
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Steffen
authors: S
authors: Jaensch
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Steven
authors: S
authors: Osselaer
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Willem
authors: W
authors: Talloen
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Ilse
authors: I
authors: Van den Wyngaert
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Geert
authors: G
authors: Van Hecke
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Dirk
authors: D
authors: Wuyts
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Freddy
authors: F
authors: Van Goethem
authors: Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Hinrich W H
authors: HW
authors: Göhlmann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055808:Drug Discovery; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D018613:Microscopy, Confocal; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D013329:Structure-Activity Relationship; D059467:Transcriptome / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
chemical_list: D010726:Phosphodiesterase Inhibitors; D011759:Pyrrolidines; D014404:Tubulin; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases