Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction |
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| Authors: | 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 Dö mling,Tad A. Holak |
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| Affiliation: | 1.Department of Drug Design, University of Groningen, 9713 AV Groningen, The Netherlands; (S.S.); (Z.W.); (B.Z.); (R.B.); (T.Z.-T.);2.Faculty of Chemistry, Jagiellonian University, 30-387 Krakow, Poland; (L.G.); (E.S.); (I.R.); (J.K.-K.); (K.M.-M.); (L.S.) |
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| Abstract: | 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. |
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| Keywords: | PD-1/PD-L1 small-molecule inhibitors immune checkpoint blockade |
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