Advancing interleukin druggability: Beyond ligandability toward therapeutic efficacy

Targeting interleukin (IL) signaling has long been constrained by the extensive, topologically flat and dynamic nature of cytokine-receptor interfaces. While monoclonal antibodies have validated these pathways clinically, achieving comparable efficacy with small molecules or non-antibody modalities demands overcoming steep pharmacokinetic and structural hurdles. In this review, we examine the translational trajectory across IL-17, IL-23, IL-1-family and IL-6 pathways-tracing compounds from in silico and biophysical hit identification to cellular and clinical validation. Rather than focusing merely on surface binding, we dissect the interplay between pocket dynamics (cryptic sites), modality selection (orally bioavailable macrocycles and traditional Rule-of-Five chemotypes) and the systemic liabilities of pathway crosstalk. These case studies provide pragmatic frameworks for converting structural ligandability into durable clinical outcomes.