2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel HDAC3 PROTACs for combined therapy with Venetoclax in acute myeloid leukemia

Design, synthesis, and biological evaluation of novel HDAC3 PROTACs for combined therapy with Venetoclax in acute myeloid leukemia

  • Bioorg Chem. 2026 Mar:170:109520. doi: 10.1016/j.bioorg.2026.109520.
Yuxin Chen 1,  Enqiang Liu 1,  Xingchun Ding 1,  Chong Qin 2,  Yuqi Jiang 3,  Xiaoyang Li 4
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
  • 2 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China.. Electronic address: [email protected].
  • 3 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China.. Electronic address: [email protected].
  • 4 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China.. Electronic address: [email protected].
PMID: 41610583 DOI: 10.1016/j.bioorg.2026.109520
Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic neoplasm driven in part by aberrant epigenetic mechanisms such as histone deacetylation, with HDAC3 playing an important role in its pathogenesis. In this study, we designed a series of novel HDAC3 PROTACs based on our previously designed HDAC3 Inhibitor as the POI ligand. Among these, representative compound B22 potently degraded HDAC3, with a DC50 of 30.73 nM and a Dmax of 82%. B22 synergized with the clinically approved AML agent Venetoclax, demonstrating potent anti-proliferative effects and significantly promoting Apoptosis in MV4-11 cells. Mechanistically, the combination of B22 and Venetoclax synergistically induces DNA damage and downregulates the anti-apoptotic proteins Mcl-1 and Bcl-xL. In conclusion, this study provided insights into novel HDAC3-directed PROTACs development and proposed their therapeutic potential against AML.

Keywords

Acute myeloid leukemia; Combined therapy; HDAC3 PROTAC; Venetoclax.

Figures
Products