Large scale profiling in human primary-cell based phenotypic assays identifies novel outcome pathways for drug efficacy in cardiovascular disease
Recorded On: 02/07/2018
We have previously identified an in vitro signature, characterized by increased cell surface levels of serum amyloid A (SAA) in a human primary cell-based coronary artery smooth muscle cell model of vascular inflammation (BioMAP CASM3C system), shared by certain compound classes associated with cardiovascular toxicity. Data mining a large reference database containing more than 4,500 test agents (drugs, experimental chemicals, etc.) profiled in this assay identified certain mechanisms to be associated with this signature: MEK inhibitors, HDAC inhibitors, GR/MR Agonists, IL-6 pathway agonists, as well as modulators of SIRT1. Since SAA is a clinical biomarker associated with risk of cardiovascular disease in humans, these results suggested that these mechanisms might contribute to cardiotoxicity by direct promotion of vascular dysfunction through SAA within vascular tissues. To further extend these studies, we mined the reference database to identify agents that decrease levels of SAA in the BioMAP CASM3C system without causing overt cytotoxicity. Notable agents that were found to decrease the cell surface level of SAA relative to vehicle control include GLP-1, an endogenous peptide developed as a drug used for treatment of diabetes, roflumilast, a PDE IV inhibitor used for the treatment of chronic obstructive pulmonary disorder, the BCR-Abl inhibitor and oncology drug, imatinib, and a mimetic of ApoA-1, the major lipoprotein of HDL. These represent agents that have been shown to have cardiovascular protective effects in clinical or in vivo studies (some within their class). The results here suggest a potential mechanism for this cardiovascular benefit through regulation of SAA, possibly through interfering with the involvement of SAA in the recruitment and activation of monocytes in the vascular wall. These findings support the value of a large chemical biology database of reference drugs profiled through primary human cell-based phenotypic assays. This database has been mined to reveal several novel associations with adverse events and identified potential mechanisms of toxicity, and here we show how this database can be used to generate new hypotheses for drug efficacy. Collectively these data support a disease and adverse outcome pathway for cardiovascular disease involving the regulation of SAA.
Ellen L. Berg, PhD, is Chief Scientific Officer at DiscoverX, BioMAP Division. She held prior positions at BioSeek and Protein Design Labs, earned her PhD from Northwestern University and was a postdoc at Stanford University. She is an SLAS fellow (Society for Laboratory Automation and Screening), a board member of ASCCT (American Society of Cellular and Computational Toxicology), and a member of the Society of Toxicology (SOT) and the Inflammation Research Association (IRA). Her research interests include human-based in vitro models of tissue and disease, chemical biology for predicting drug and toxicity mechanisms of action and phenotypic drug discovery. Dr. Berg holds a number of patents in the field of inflammation and has authored >80 publications.