Preclinical Characterization of SDFZ-8, a Highly Potent HDAC1 Inhibitor, for Cancer Immunotherapy.

The histone deacetylases (HDACs) family plays a critical role in tumorigenesis and has been identified as having a significant impact on tumor immunity. Herein, we employed a fragment-centric structure-based design platform, leading to the discovery of SDFZ-8 as a highly potent HDAC1 inhibitor (IC(50) = 0.4 nM). SDFZ-8 exhibits strong antiproliferative effects by enabling histone acetylation and inducing cell apoptosis. Crucially, SDFZ-8 treatment led to a significant enhancement of antitumor immunity, as evidenced by increased activation of T cells, enhanced polarization of M1-type macrophages, improved antigen presentation, and alleviation of the immunosuppressive tumor microenvironment. Specifically, we observed that SDFZ-8 notably upregulated the expression of PD-L1 in both tumor cells and tumor-infiltrating lymphocytes, which is closely associated with its inhibition against HDAC1. Of particular interest, combining SDFZ-8 with PD-L1 blockade resulted in a synergistic antitumor effect surpassing that of either monotherapy. Taken together, our findings establish SDFZ-8 as a novel HDAC1 inhibitor that concurrently targets tumor cells and immune evasion mechanisms, providing a rational combinatorial strategy to enhance cancer immunotherapy efficacy.