TY  - JOUR
AU  - Prescher, Horst
AU  - Frank, Martin
AU  - Gütgemann, Stephan
AU  - Kuhfeldt, Elena
AU  - Schweizer, Astrid
AU  - Nitschke, Lars
AU  - Watzl, Carsten
AU  - Brossmer, Reinhard
TI  - Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec-7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion.
JO  - Journal of medicinal chemistry
VL  - 60
IS  - 3
SN  - 1520-4804
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2017-00424
SP  - 941 - 956
PY  - 2017
AB  - 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 cell immune evasion. The compounds are Sialic acid derivatives and bind with low micromolar Kd values to Siglec-7. They display up to a 5000-fold enhanced affinity over the unmodified sialic acid scaffold αMe Neu5Ac, the smallest known natural Siglec-7 ligand. Our results provide a novel immuno-oncology strategy employing natural immunity in the fight against cancers, in particular blocking Siglec-7 with low molecular weight compounds.
LB  - PUB:(DE-HGF)16
C6  - pmid:28103033
DO  - DOI:10.1021/acs.jmedchem.6b01111
UR  - https://inrepo02.dkfz.de/record/119829
ER  -