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Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Artemisinin-derived hydrophobic tags: structural modification and structure-activity relationship exploration of
Changqi Wang1, Qiying Yu2, Xing Lu1
1Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals, School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, PR China.
Abstract:
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.
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