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. 2022 Jul 12;65(14):9858–9872. doi: 10.1021/acs.jmedchem.2c00505

Figure 1.

Figure 1

First Nectin-4/CD137 Bicycle TICA demonstrates Nectin-4-dependent CD137 agonism. (A) Schematic illustration of Nectin-4-dependent CD137 agonism induced by BCY8854. (B) Structure of BCY8854 with a linker composed of Peg12 and Sar10 and affinities to CD137 and Nectin-4 as measured by SPR. (C) CD137 reporter coculture assay activity with MC38 (Nectin-4 negative) or MC38-Nectin-4 tumor cells after treatment for 6 h with BCY8854. Data are mean (n = 2 replicates). (D) Pictorial representation of BCY10000, where Nectin-4 bicycle, linker, and attachment point are the same as BCY8854, but the CD137 bicycle is replaced with higher affinity analogue. The binding affinities (KD) to CD137 and Nectin-4 as measured by SPR are also shown. (E) HT1376/CD137 reporter coculture assay activity of BCY8854 and BCY10000. Data are mean ± s.d (n = 3 replicates) and represented as fold induction over the background of a luciferase reporter gene driven by an element that responds to CD137 stimulation. Data in panels (C) and (E) were fit using log (agonist) vs response–variable slope (four parameters) in GraphPad Prism V.8.4.3.