The benchmarking and application of tag-degraders in vivo to validate therapeutic targets
- Author(s)
- Magtoto, CM; Mieruszynski, S; Dong, H; Ng, AP; Di Rago, L; Kueh, AJ; Brzozowski, M; Grohmann, C; Walker, JR; Chua, NK; Dagley, LF; Ciulli, A; Lessene, G; Herold, MJ; Heath, JK; Silke, J; Feltham, R;
- Journal Title
- Nature Communications
- Publication Type
- Online publication before print
- Abstract
- Transitioning a candidate therapeutic target from bench to bedside requires significant time and financial investment, yet clinical success remains low often due to poor on-target toxicity assessment during preclinical validation. Tag-degraders provide a tool to improve target validation by enabling degradation of any protein of interest via a degron-tag. This drug-based, reversible, and dose-dependent method of protein removal can mimic degrader-based drug treatments and assess the implications of target protein depletion in vivo. However, each degrader has a distinct pharmacokinetic profile that will influence its effectiveness across tissues. To create a resource to enable the most appropriate choice of tag-degrader, we benchmark the dTAG, HaloPROTAC, and NanoTAC systems in vivo by employing a transgenic mouse expressing a reporter protein targetable by these tag-degraders. Through various treatment regimes, we characterise each degrader profile across a panel of 20 tissues and organs, highlighting the superior degradation by dTAG molecules, and identify differences between degradation in whole tissues versus single cell populations. Using an FKBP(F36V) knock-in mouse expressing 65K-FKBP(F36V), we reveal target specific degradation kinetics, and a critical requirement for 65K in mice. Together, this resource will assist researchers in choosing the right degrader and tag for their own applications.
- Department(s)
- Haematology
- Publisher's Version
- https://doi.org/10.1038/s41467-026-73681-1
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-026-73681-1- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-06-04 11:59:38
Last Modified: 2026-06-04 12:00:13