PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

Abstract

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.

Leveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1

“…For the Free-Wilson analysis, the 3-(Phenoxymethyl)biphenyl scaffold was considered as a core scaffold for the selected dataset, and seven R groups substitutions sites were determined on this core. Although many novel and potent BMS-like scaffolds have been recently disclosed by several groups that are actively working in the field [ 58 , 59 ], the scarcity of available datasets prevented us from performing similar analyses for these scaffolds. We are currently working on collecting more data on these scaffolds and the results will be presented in future studies.…”

Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors

“…To determine the potency of synthesized inhibitors to disrupt the PD-1/PD-L1 complex, we used homogeneous time resolved fluorescence (HTRF), which is a well-established method for the inhibitory activity of PD-L1 assessment based on RT-FRET effect. ,,, In this binding assay, tagged PD-1 and PD-L1 are labelled with anti-tag reagent that generates FRET signal only when both proteins are bound (in spatial proximity). Presence of inhibitors (small molecules, proteins, and so forth) that disrupt the binding decreases the resulting signal allowing the assessment of the inhibitory activity of tested inhibitors via IC 50 (the half maximal inhibitory concentration).…”

Development of Radiotracers for Imaging of the PD-1/PD-L1 Axis

“…We have adopted this concept for PD-L1-targeting small molecules and introduced the chelator via a hydrophilic linker unit [128]. In the past years, biological studies have revealed that the binding mode of small molecule inhibitors differs significantly from that of antibodies and peptides (Figure 16) [129]. While both antibodies and peptides bind in a 1:1 molar ratio to PD-L1 and thus prevent the binding of the natural ligand PD-1 in an antagonistic manner, biphenyl- derived low-molecular weight compounds recruit two PD-L1 proteins, leading to the dimerization of the human PD-L1 in vitro.…”