HDAC3 inhibitors(Birla Institute of Technology & Science)

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 D_max 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.

Histone deacetylase 3 (HDAC3) is a key epigenetic regulator implicated in breast cancer progression and represents a promising therapeutic target. Here, we investigated 14 HDAC3-ligand complexes using molecular dynamics (MD) simulations and binding free energy calculations (MM/GBSA) to identify the determinants of inhibitor binding. Key residues consistently engaged across ligands included Gly132, His134-135, Phe144, Asp170, His172, Phe200, Asp259, Leu266, Gly296, Tyr298, and the catalytic Zn²⁺ ion. Among the compounds, domatinostat and entinostat exhibited the strongest affinities (ΔGbind ≈ -70 kcal/mol), in reasonable agreement with experimental data (r = 0.60). Both ligands also showed small Highest Occupied Molecular Orbital-Lowest Unoccupied Molecular Orbital (HOMO-LUMO) gaps, high softness, and elevated electrophilicity indices, providing chemical cues for the design of next-generation HDAC3 inhibitors. Notably, ligand binding stabilized regions surrounding Phe200 and Asn370, restricting the conformational flexibility required for enzymatic activation. This supports an allosteric inhibition mechanism in which ligands lock HDAC3 into inactive conformations. Collectively, these findings offer mechanistic insights into HDAC3 regulation and highlight structural hot spots for the rational design of selective inhibitors with potential applications in targeted breast cancer therapy.