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

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.