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

Prescher H, Frank M, Guetgemann S, Kuhfeldt E, Schweizer A, Nitschke L, Watzl C, Brossmer R (2017)

Publication Status: Published

Publication Type: Journal article

Publication year: 2017

Journal

Journal of Medicinal Chemistry American Chemical Society

Publisher: AMER CHEMICAL SOC

Book Volume: 60

Pages Range: 941-956

Journal Issue: 3

DOI: 10.1021/acs.jmedchem.6b01111

Abstract

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:

Authors with CRIS profile

Astrid Schweizer Lars Nitschke Professur für Genetik

Involved external institutions

Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite

APA:

Prescher, H., Frank, M., Guetgemann, S., Kuhfeldt, E., Schweizer, A., Nitschke, L.,... Brossmer, R. (2017). Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec-7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion. Journal of Medicinal Chemistry, 60(3), 941-956. https://doi.org/10.1021/acs.jmedchem.6b01111

MLA:

Prescher, Horst, et al. "Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec-7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion." Journal of Medicinal Chemistry 60.3 (2017): 941-956.

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