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<p>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<sup>F36V</sup> knock-in mouse expressing 65K-FKBP<sup>F36V</sup>, we reveal target specific degradation kinetics, and a critical requirement for&#xa0;65K in mice. Together, this resource will assist researchers in choosing the right degrader and tag for their own applications.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月29日

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  • Charlene M. Magtoto,
  • Stephen Mieruszynski,
  • Hao Dong,
  • Ashley P. Ng,
  • Ladina Di Rago,
  • Andrew J. Kueh,
  • Martin Brzozowski,
  • Christoph Grohmann,
  • Joel R. Walker,
  • Ngee Kiat Chua,
  • Laura F. Dagley,
  • Alessio Ciulli,
  • Guillaume Lessene,
  • Marco J. Herold,
  • Joan K. Heath,
  • John Silke,
  • Rebecca Feltham

摘要

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.