Identification and Validation of New Interleukin‑2 Ligands Using DNA-Encoded Libraries

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.