The benchmarking and application of tag-degraders in vivo to validate therapeutic targets

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

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;
Details: Publication Year 2026-05-29,Volume 17,Issue #1,Page 7001
Journal Title: Nature Communications
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.
Publisher: Springer Nature
Keywords: Animals; Mice, Transgenic; Mice; Humans; *Proteolysis/drug effects; Proteolysis Targeting Chimera; Benchmarking; Degrons
Research Division(s): Ubiquitin Signalling; Immunology; Blood Cells and Blood Cancer; New Medicines and Diagnostics; Advanced Technology and Biology; Genetics and Gene Regulation
PubMed ID: 42215500
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: 2026-06-10 01:51:14

Last Modified: 2026-07-30 09:26:02