Publication date: Apr 15, 2025
Targeting programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has been considered as one of the most promising strategies for tumor immunotherapy. However, single-target PD-1/PD-L1 inhibitors frequently exhibit limited efficacy, highlighting the urgent need for new therapies. Herein, a series of dual PD-L1/HDAC3 inhibitors were developed through a pharmacophore fusion strategy for the first time. Among them, compound PH3 was identified as the most promising dual PD-L1/HDAC3 inhibitor, with potent PD-1/PD-L1 inhibitory activity (IC = 89. 4 nM) and selective HDAC3 inhibitory activity (IC = 107 nM). Moreover, PH3 exhibited superior in vitro antitumor activities and in vitro immune activation effects. Additionally, PH3 showed potent and dose-dependent antitumor efficacy in the B16-F10 melanoma mouse model without obvious toxicity. Furthermore, PH3 increased the infiltration of CD3CD8 and CD3CD4 cells in the tumor microenvironment. Collectively, PH3 represented a novel dual PD-L1/HDAC3 inhibitor deserving further investigation as a tumor immunotherapy agent.
| Concepts | Keywords |
|---|---|
| Cd3cd4 | Death |
| Deserving | Dual |
| F10 | Efficacy |
| Pharmacophore | Hdac3 |
| Tumor | Immunotherapy |
| Inhibitor | |
| Inhibitors | |
| Inhibitory | |
| L1 | |
| Pd | |
| Ph3 | |
| Potent | |
| Programmed | |
| Promising | |
| Tumor |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | Tumor |
| pathway | REACTOME | Programmed Cell Death |
| disease | MESH | melanoma |
| pathway | KEGG | Melanoma |