Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec-7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion

Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately,, many cancer-cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape-strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed On the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and:evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer tell immune evasion. The compounds are Sialic acid derivatives and bind with low inicromolar K-d values to Siglec-7. They display up to a 5000-fold enhanced affinity over the unmodified sight acid scaffold alpha Me NeuSAc, the smallest known natural Siglec-7 ligand. Our results provide-a novel imanuno-oncology strategy employing natural immunity in the fight against cancers, in particular-blocking Siglec-7 with low:molecular weight compounds: