Discovery of Novel HDAC3 Inhibitors with PD-L1 Downregulating/Degrading and Antitumor Immune Effects

Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising Cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC₅₀ = 89 nM) and remarkable PD-L1-degrading activity (DC₅₀ = 5.7 μM, D_max = 80% at 10 μM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating Cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3⁺ CD4⁺ helper T and CD3⁺ CD8⁺ cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD₅₀ > 1000 mg/kg) and favorable pharmacokinetic properties (F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.