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 showed selective HDAC3 inhibition (IC = 89 nM) and remarkable PD-L1-degrading activity (DC = 5.7 μM, = 80% at 10 μM). Further studies revealed that induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, could enhance the infiltration of CD3 CD4 helper T and CD3 CD8 cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, possessed a benign toxicity profile (LD > 1000 mg/kg) and favorable pharmacokinetic properties ( = 57%). Taken together, is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.