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

Area of Science:

• Oncology
• Immunology
• Medicinal Chemistry

Background:

• Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is a key cancer immunotherapy strategy.
• Histone deacetylase (HDAC) inhibitors can enhance anti-tumor immunity by modulating PD-L1 expression.

Purpose of the Study:

• To design and synthesize novel hydrazide-based small molecule HDAC inhibitors.
• To evaluate the efficacy of these compounds in degrading PD-L1 and enhancing anti-tumor immune responses.

Main Methods:

• Synthesis of novel hydrazide-based HDAC inhibitors.
• In vitro assays to determine HDAC3 inhibition and PD-L1 degradation.
• Assessment of T-cell infiltration and immune microenvironment activation.
• Evaluation of toxicity and pharmacokinetic properties.

Main Results:

• Compound HQ-30 demonstrated selective HDAC3 inhibition (IC50 = 89 nM) and potent PD-L1 degradation (DC50 = 5.7 μM).
• HQ-30 induced PD-L1 degradation via cathepsin B regulation in lysosomes.
• HQ-30 enhanced CD3+ CD4+ and CD3+ CD8+ T-cell infiltration, activating the tumor immune microenvironment.
• HQ-30 exhibited a favorable toxicity profile (LD50 > 1000 mg/kg) and good pharmacokinetic properties (F = 57%).

Conclusions:

• HQ-30 is a potent small molecule epigenetic modulator with significant anti-tumor immune-activating properties.
• HQ-30 warrants further investigation as a novel therapeutic agent for cancer immunotherapy.