Discovery of Novel Hydrazide-Based HDAC3 Inhibitors as Epigenetic Immunomodulators for Cancer Immunotherapy

Based on our previous work, a series of imidazole-based small molecules were designed and synthesized as HDAC3 inhibitors. Among them, compound SC26 showed selective HDAC3 inhibition activity with an IC₅₀ of 53 nM (SI = 75 for HDAC3 over HDAC1). Further studies revealed that SC26 could dose-dependently induce the expression of PD-L1 in MC38 cells by activating the PD-L1 transcription. SC26 also showed high in vivo antitumor efficacy in a colorectal cancer model (50 mg/kg po, TGI = 63%). Importantly, the combination of SC26 with the PD-L1 inhibitor NP19 activated the immune system in tumor-bearing mice, enhancing the antitumor immune response (TGI = 80%, 50 + 50 mg/kg, p.o.). Collectively, we report for the first time that an HDAC3 inhibitor could upregulate PD-L1 expression in vitro and in vivo, specifically in MC38 cells and MC38-bearing tumors, and SC26 represents a novel epigenetic immunomodulator with potential applications in tumor immunotherapy.