Sheila Dakhel; Andrea Galbiati; Francesca Migliorini; Claudia Comacchio; Sebastian Oehler; Luca Prati; Jörg Scheuermann, Samuele Cazzamalli; Dario Neri, Gabriele Bassi; Nicholas Favalli
ChemMedChem, 2022, e202200350
https://doi.org/10.1002/cmdc.202200350

Abstract

Natural Killer Group 2D (NKG2D) is a homo-dimeric transmembrane protein which is typically expressed on the surface of natural killer (NK) cells, natural killer T (NKT) cells, gamma delta T (γδT) cells, activated CD8 positive T-cells and activated macrophages. Bispecific molecules, capable of bridging NKG2D with a target protein expressed on the surface of tumor cells, may be used to redirect the cytotoxic activity of NK-cells towards antigen-positive malignanT-cells. In this work, we report the discovery of a novel NKG2D small molecule binder [K D = (410±60) nM], isolated from a DNA-Encoded Chemical Library (DEL). The discovery of small organic NKG2D ligands may facilitate the generation of fully synthetic bispecific adaptors, which may serve as an alternative to bispecific antibody products and which may benefit from better tumor targeting properties.