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Identification and Validation of New Interleukin-2 Ligands Using DNA-Encoded Libraries
Journal of Medicinal Chemistry  (IF7.446),  Pub Date : 2021-11-25, DOI: 10.1021/acs.jmedchem.1c01693
Adrián Gironda-Martínez, Émile M. D. Gorre, Luca Prati, Jean-François Gosalbes, Sheila Dakhel, Samuele Cazzamalli, Florent Samain, Etienne J. Donckele, Dario Neri

Interleukin-2 (IL2) is a pro-inflammatory cytokine that plays a crucial role in immunity, which is increasingly being used for therapeutic applications. There is growing interest in developing IL2-based therapeutics which do not interact with the alpha subunit of the IL2 receptor (CD25) as this protein is primarily found on immunosuppressive regulatory T cells (Tregs). Screenings of a new DNA-encoded library, comprising 669,240 members, provided a novel series of IL2 ligands, subsequently optimized by medicinal chemistry. One of these molecules (compound 18) bound to IL2 with a dissociation constant of 0.34 μM was able to form a kinetically stable complex with IL2 in size-exclusion chromatography and recognized the CD25-binding site as evidenced by competition experiments with the NARA1 antibody. Compound 18 and other members of the series may represent the starting point for the discovery of potent small-molecule modulators of IL2 activity, abrogating the binding to CD25.