Enzymes in secondary pharmacology screening panels: is there room for improvement?

Abstract

A recent article by Brennan and colleagues (Nat. Rev. Drug Discov. 23, 525–545; 2024)¹ presents the findings of the largest collaborative effort among leading pharmaceutical companies on the application of secondary pharmacology screening to identify off-target activities of drug candidates, showing that wider adoption of standardized selectivity profiling has positively affected the safety of newer small-molecule drugs. The authors recommend an expanded panel of off-targets that is partly based on two earlier panels proposed by Bowes et al.² and Lynch et al.³. We applaud Brennan and colleagues for completing this important collaborative work and expect their study will impact drug development substantially. Nevertheless, we want to use this opportunity to discuss an overlooked issue of non-kinase enzyme representation in the screening panels recommended thus far.

The three noted panels include a partially overlapping set of targets associated with well-characterized safety concerns and are comprised of 44 (Bowes-44)², 70 (Lynch-70)³, and 77 (Brennan-77)¹ targets, covering the main pharmacological classes. Regarding enzymes, these panels only include 6 to 9 non-kinase enzymes, comprising 12% of all targets in the latest Brennan-77 panel (Fig. 1c). Since enzymes are a leading category for the ‘to-be’ and currently approved drugs, it is surprising that the share of enzymes in selectivity panels remains so limited. This underrepresentation is further highlighted by a recent study from Amgen showing the involvement of enzymes in about one-third of drug-related adverse events (23% non-kinase enzymes and 10% kinases)⁴. Similarly, an FDA study on the secondary pharmacology of investigational new drugs concluded that enzymes are tested less frequently than other targets despite comparable or higher hit rates⁵.