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

Nature Reviews Drug Discovery volume 24, pages 482–484 (2025)Cite this article

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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).

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Fig. 1: Coverage of the Safety-77 panel.

References

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Acknowledgements

The authors thank E. Pawluk from UCB for developing Fig. 1a and all members of the IQ-DruSafe In vitro Secondary Pharmacology Working Group for their contribution. J-P.V. and F.S. are the current Chair and Co-Chair of the IQ-DruSafe In vitro Secondary Pharmacology Working Group, respectively, whereas R.J.B. and S.J. are former Co-Chairs.

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Authors and Affiliations

  1. Sanofi, Frankfurt, Germany

    Friedemann Schmidt

  2. Sanofi, Cambridge, MA, USA

    Richard J. Brennan

  3. Pfizer, La Jolla, CA, USA

    Steve Jenkinson

  4. UCB, Braine-l’Alleud, Belgium

    Jean-Pierre Valentin

Authors
  1. Friedemann Schmidt
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  2. Richard J. Brennan
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  3. Steve Jenkinson
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  4. Jean-Pierre Valentin
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Corresponding author

Correspondence to Friedemann Schmidt.

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Competing interests

F.S. and J.-P.V. are employees of pharmaceutical companies. S.J. is an employee of Metrion Biosciences, a CRO providing screening services to pharmaceutical companies. F.S., R.J.B., S.J. and J.-P.V. may hold shares, share rights and/or stock options in pharmaceutical companies.

Additional information

Related links

Assessment of Pressor Effects of Drugs Guidance for Industry | FDA: http://www.fda.gov/media/113477/download

Commission acts to accelerate phasing out of animal testing in response to a European Citizens’ Initiative (accessed on 21 January 2025): https://ec.europa.eu/commission/presscorner/detail/en/ip_23_3993

FDA Guidance for Industry on the Assessment of Abuse Potential of Drugs: https://www.fda.gov/media/116739/download

H.R.7248 - FDA Modernization Act 3.0. 118th Congress (2023–2024) (accessed on 21 January 2025): https://www.congress.gov/bill/118th-congress/house-bill/7248

Official webpage of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH): https://www.ich.org/page/safety-guidelines

The principles of the 3Rs (replacement, reduction and refinement): https://www.nc3rs.org.uk/who-we-are/3rs

The Translational Value of Secondary Pharmacology Binding Assays for Nonclinical Findings: https://www.fda.gov/media/168854/download

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Schmidt, F., Brennan, R.J., Jenkinson, S. et al. Shaping secondary pharmacology panels of the future: evolving target selection criteria for safety panels. Nat Rev Drug Discov 24, 482–484 (2025). https://doi.org/10.1038/s41573-025-01184-7

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