Design, synthesis, and evaluation of PD-1/PD-L1 small-molecule inhibitors bearing a rigid indane scaffold

by Selleckchem | Jul 04 2023

Discovery of small-molecule inhibitors against programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis provides a promising alternative to overcome the inevitable defects of PD-1/PD-L1 monoclonal antibodies (mAbs). Here, we report a series of indanes as novel small-molecule inhibitors of PD-1/PD-L1 interaction. Thirty-one indanes were synthesized and the structure-activity relationships (SARs) demonstrated that conformational restriction with (S)-indane is superior in potency to inhibit the interaction of PD-1 and PD-L1. Compound D3 was found to be the most potent inhibitor with an IC50 value of 2.2 nM against PD-1/PD-L1 interaction. Cell-based assay showed that D3 significantly induced immune activity of peripheral blood mononuclear cells (PBMCs) against MDA-MB-231 cells and could restore the immune function of T cells by promoting secretion of the IFN-γ. The above results indicate that compound D3 is a promising PD-1/PD-L1 inhibitor that deserves further development.

Comments:

The discovery of small-molecule inhibitors targeting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis is an exciting development in the field of immunotherapy. These inhibitors offer a potential alternative to monoclonal antibodies (mAbs) that target PD-1/PD-L1, addressing some of the limitations associated with antibody-based therapies. In this study, a series of indane compounds were synthesized and evaluated for their ability to inhibit the interaction between PD-1 and PD-L1.

The researchers synthesized thirty-one indane compounds and conducted structure-activity relationship (SAR) studies to understand the relationship between the chemical structure of the indanes and their inhibitory potency against PD-1/PD-L1 interaction. The SAR analysis revealed that conformational restriction using (S)-indane resulted in compounds with higher potency in inhibiting the interaction between PD-1 and PD-L1.

Among the synthesized compounds, compound D3 exhibited the most potent inhibitory activity, with an IC50 value of 2.2 nM against the PD-1/PD-L1 interaction. To further evaluate the potential of D3 as a PD-1/PD-L1 inhibitor, a cell-based assay was conducted. The assay demonstrated that D3 significantly enhanced the immune activity of peripheral blood mononuclear cells (PBMCs) against MDA-MB-231 cells, indicating its ability to promote anti-tumor immune responses. Additionally, D3 was found to restore the immune function of T cells by stimulating the secretion of interferon-gamma (IFN-γ), a key cytokine involved in immune responses.

Based on these findings, compound D3 shows great promise as a small-molecule inhibitor of the PD-1/PD-L1 axis. It exhibits potent inhibitory activity against the PD-1/PD-L1 interaction and demonstrates the ability to enhance immune responses against cancer cells. These results suggest that D3 warrants further development as a potential therapeutic agent for immunotherapy, potentially offering advantages over PD-1/PD-L1 monoclonal antibodies.