Discovery of Dual PD-L1/HDAC3 Inhibitors for Tumor Immunotherapy

Area of Science:

• Oncology
• Immunology
• Medicinal Chemistry

Background:

• Targeting the programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway is a key strategy in cancer immunotherapy.
• Limited efficacy of single-target PD-1/PD-L1 inhibitors necessitates the development of novel therapeutic approaches.

Purpose of the Study:

• To develop novel dual inhibitors targeting both PD-L1 and Histone Deacetylase 3 (HDAC3) for enhanced tumor immunotherapy.
• To identify and characterize a lead compound with potent dual inhibitory activity and evaluate its therapeutic potential.

Main Methods:

• A pharmacophore fusion strategy was employed to design and synthesize a series of dual PD-L1/HDAC3 inhibitors.
• Compound PH3 was identified and evaluated for its inhibitory activity against PD-L1 and HDAC3 using biochemical assays.
• In vitro antitumor activities, immune activation effects, and in vivo efficacy in a B16-F10 melanoma mouse model were assessed.

Main Results:

• Compound PH3 demonstrated potent inhibition of PD-L1 (IC50 = 89.4 nM) and selective inhibition of HDAC3 (IC50 = 107 nM).
• PH3 exhibited significant in vitro antitumor effects and immune-stimulatory properties.
• In vivo studies showed potent and dose-dependent antitumor efficacy of PH3 in a melanoma mouse model with no apparent toxicity.
• PH3 treatment led to increased infiltration of CD3+CD8+ and CD3+CD4+ immune cells within the tumor microenvironment.

Conclusions:

• Compound PH3 represents a novel and promising dual PD-L1/HDAC3 inhibitor.
• The dual-targeting strategy warrants further investigation for its potential as an effective agent in cancer immunotherapy.