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

TY - JOUR

T1 - The benchmarking and application of tag-degraders in vivo to validate therapeutic targets

AU - Magtoto, Charlene M

AU - Mieruszynski, Stephen

AU - Dong, Hao

AU - Ng, Ashley P

AU - Di Rago, Ladina

AU - Kueh, Andrew J

AU - Brzozowski, Martin

AU - Grohmann, Christoph

AU - Walker, Joel R

AU - Chua, Ngee Kiat

AU - Dagley, Laura F

AU - Ciulli, Alessio

AU - Lessene, Guillaume

AU - Herold, Marco J

AU - Heath, Joan K

AU - Silke, John

AU - Feltham, Rebecca

N1 - © 2026. The Author(s).

PY - 2026/7/23

Y1 - 2026/7/23

N2 - 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 FKBPF36V knock-in mouse expressing 65K-FKBPF36V, 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.

AB - 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 FKBPF36V knock-in mouse expressing 65K-FKBPF36V, 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.

UR - https://www.scopus.com/pages/publications/105045548846

U2 - 10.1038/s41467-026-73681-1

DO - 10.1038/s41467-026-73681-1

M3 - Article

C2 - 42215500

SN - 2041-1723

VL - 17

JO - Nature Communications

JF - Nature Communications

M1 - 7001

ER -