Shaping secondary pharmacology panels of the future: evolving target selection criteria for safety panels

We appreciate the thoughtful commentary by Maciag and Karamyan¹ on our 2024 publication ‘The state of the art in secondary pharmacology and its impact on the safety of new medicines’². In this paper, we reviewed secondary pharmacology data and profiling strategies from 18 pharmaceutical companies and recommended the implementation of an expanded core safety panel consisting of 77 diverse targets (Safety-77). The main aim of such screening panels is to identify potential human safety liabilities of novel molecules across all indications and chemotypes. To serve its purpose, the panel was balanced with respect to diversity of target families and mechanisms of toxicities, but it was also kept feasible with respect to its size.

Maciag and Karamyan highlight the underrepresentation of non-kinase enzymes in our recommended assay panels and suggest the consideration of non-kinase enzymes such as neprilysin, cathepsins, carbonic anhydrases, thromboxane A synthase and xanthine oxidase due to risks of adverse events associated with activity against these enzymes. Studies by regulatory agencies have shown that inhibition of enzymes could be implicated in adverse events and that enzymes have comparable or higher hit rates than other targets (see Related links).