State-of-the-art in secondary pharmacology and its impact on the safety of new medicines

Abstract

Adverse effects of drugs often result from unexpected drug-off-target interactions triggering secondary pharmacology (2P). Consequently, 2P profiling of new chemical entities across a range of protein targets is a routine task in pharmaceutical R&D. Particularly targets with known association to safety adverse events (e.g., GPCRs, ion channels, transporters, protein kinases and other enzymes) are considered. However, there is significant variability across pharmaceutical industry in the composition of target panels screened, assay technologies implemented, and in the timing and scheduling of 2P screening efforts. As part of the IQ DruSafe consortium, a 2P working group was established, comprising representatives from 18 companies, to conduct a review of 2P strategies and share experiences, to recommend best practices and future application for the industry. Member companies contributed proprietary data across parameters such as target panel composition, position in the R&D process, sourcing of the panels, the assay types and technology used. Performance and outcome, including total number of compounds run, concentrations tested, and hit rates, were also recorded. A detailed database capturing an overview of the strategic, scientific, and operational aspects of 2P screening has been created accordingly. This database currently holds 3729 records detailing on assays covering 747 distinct biological targets that are assessed for 2P. Conclusions will be presented highlighting some key trends that should be considered for future evolution of 2P practices across the industry. The working group identified a strong influence of previous published work on 2P panel composition by Bowes et al. 2012 and Lynch et al., 2017 with high prevalence of the targets they propose applied across the industry, but also a set of uncommon targets has been identified that should be considered from a safety perspective. Furthermore, given the recent broadening in pharmaceutical targets by precision medicine approaches, extending the coverage of 2P previously under-represented target classes such as protein kinases, enzyme families and epigenetic targets appears to be important.

Bowes et al. 2012, Bowes, J., Brown, A. J., Hamon, J., Jarolimek, W., Sridhar, A., Waldron, G., & Whitebread, S. (2012). Reducing safety-related drug attrition: The use of in vitro pharmacological profiling. Nature Reviews: Drug Discovery, 11(12), 909–922.

Lynch, J. J., Vleet, T. R. V., Mittelstadt, S. W., & Blomme, A. G. (2017). Potential functional and pathological side effects related to off-target pharmacological activity. Journal of Pharmacological and Toxicological Methods, 87, 108–126.