Phenotypic Approaches Defining Toxicity Mechanisms

Phenotypic Approaches Defining Toxicity Mechanisms

File Name/Number:
2013 DDI_RnI


We have applied a panel of primary human cell-based in vitro systems (the BioMAP® systems platform) that model complex aspects of disease and tissue biology to investigate the biological mechanisms that underlie certain drug adverse effects. Here we present the analysis of several anti-inflammatory kinase inhibitors in development, including inhibitors of Jak kinase (tofacitinib) and syk kinase (fostamatinib). Specific activities of these compounds, when tested in a panel of 12 BioMAP® systems, Diversity PLUS panel, covering a broad range of human biology that model processes important to vascular function and wound healing responses, led to mechanistic hypotheses underlying certain side effects of these drugs in patients. These side effects include gastrointestinal perforations (Jak) and hypertension (syk). A better understanding of the potential toxicity mechanisms underlying these adverse effects may be helpful in guiding future clinical development. These results support the use of phenotypic in vitro approaches to help prioritize drug candidates prior to testing in humans, and more broadly, for defining toxicity mechanisms relevant to chemical safety.