Artemisinin-derived hydrophobic tags: structural modification and structure-activity relationship exploration of HDAC6/1 targeting degraders with potent antileukemic efficacy.

Hydrophobic tags (HyTs) in targeted protein degradation (TPD) offer a novel strategy to address HDAC off-target effects and drug resistance in hematological cancers. Artemisinin derivatives，characterized by their unique and highly hydrophobic endoperoxide bridge, emerge as promising candidates for HyTs development. However, the structure-activity relationship has not been systematically investigated. Herein, we conjugateddiverse artemisinin analogs (including D-ring-contracted artemisinin, deoxyartemisinin, and monocyclic endoperoxide derivatives) with the hydroxamic acid pharmacophore of SAHA to generate a series of HDAC degraders. We identified that the endoperoxide bridge of artemisinin derivatives is critical for degradation activity. The lead compound Q5 displays exceptional degradation efficacy in MOLT-4 cells, achieving a DC50 value of 6.375 μM for HDAC6 and a Dmax value of 87.31%. This research establishes a foundational framework for the optimization of artemisinin-based HyTs, and introduces a novel application of artemisinin derivatives in the field of TPD.