Discovery of D‑Ring-Contracted Artemisinin as a Potent Hydrophobic Tag for Targeted Protein Degradation

The relentless pursuit of innovative hydrophobic tags
remains a
formidable challenge within the realm of targeted protein degradation.
Herein, we have uncovered the remarkable potential of D-ring-contracted
artemisinin as a potent hydrophobic tag that demonstrates exceptional
degradation efficiency. We have crafted a series of conjugates by
fusing D-ring-contracted artemisinin with raloxifene, and among these, RA3 has emerged as a promising candidate for degrading estrogen
receptor α (ERα). In a breast cancer xenograft mouse model, RA3 induced pronounced tumor growth inhibition, surpassing
the performance of the FDA-approved ERα degrader, Faslodex.
Furthermore, the versatility of D-ring-contracted artemisinin as a
hydrophobic tag has been confirmed in its ability to enhance the degradation
of cyclin-dependent kinase 6 (CDK6) and histone deacetylases (HDACs).
Our work not only underscores the therapeutic potential of artemisinin
derivatives in targeted protein degradation but also paves new avenues
for advancing the field of protein-based drug design.