Discovery of D-Ring-Contracted Artemisinin as a Potent Hydrophobic Tag for Targeted Protein Degradation
Luolong Qing, Qiying Yu, Changqi Wang, Xing Lu, Yuanli Yang, Xiao Chen, Xiangxiang Li, Jian Min, Weidong Pan, Huan He, Hang Zhong, Silong Zhang
Abstract
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.