Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

Shabnam Shaabani*, Louis Gadina, Ewa Surmiak, Zefeng Wang, Bidong Zhang, Roberto Butera, Tryfon Zarganes-Tzitzikas, Ismael Rodriguez, Justyna Kocik-Krol, Katarzyna Magiera-Mularz, Lukasz Skalniak, Alexander Dömling, Tad A Holak

*Bijbehorende auteur voor dit werk

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New biphenyl-based chimeric compounds containing pomalidomide were developed and evaluated for their activity to inhibit and degrade the programmed cell death-1/programmed cell death- ligand 1 (PD-1/PD-L1) complex. Most of the compounds displayed excellent inhibitory activity against PD-1/PD-L1, as assessed by the homogenous time-resolved fluorescence (HTRF) binding assay. Among them, compound 3 is one of the best with an IC50 value of 60 nM. Using an ex vivo PD-1/PD-L1 blockade cell line bioassay that expresses human PD-1 and PD-L1, we show that compounds 4 and 5 significantly restore the repressed immunity in this co-culture model. Western blot data, however, demonstrated that these anti-PD-L1/pomalidomide chimeras could not reduce the protein levels of PD-L1.

Originele taal-2English
Artikelnummer3454
Aantal pagina's17
TijdschriftMolecules
Volume27
Nummer van het tijdschrift11
DOI's
StatusPublished - 2022

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