In This Issue, Volume 16, Issue 11

Aberrant interleukin-17A (IL-17A) signaling is critically involved in the pathogenesis of several immune-mediated inflammatory diseases, as demonstrated by the therapeutic success of anti-IL-17A monoclonal antibodies in conditions such as moderate-to-severe plaque psoriasis, psoriatic arthritis, and related disorders.Although substantial effort has been invested in developing orally bioavailable agents to inhibit the IL-17A/IL-17RA cytokine-receptor interface, approaches using small molecules, peptides, and macrocyclic inhibitors have encountered notable clinical challenges, particularly poor oral bioavailability and unfavorable safety profiles.Consequently, there remains a strong need for the discovery of novel inhibitors capable of effectively and safely targeting this key protein-protein interaction.In this study (DOI: 10.1021/acsmedchemlett.5c00502), Lumb et al. identified a novel small-molecule lead (compound 1) from a DNA-encoded library screen that effectively disrupted IL-17A binding to its cognate receptor IL-17RA.Subsequent characterization confirmed binding of compound 1 to the IL-17A homodimer and, NMR analyses revealed perturbations of residues outside of the known PPI interface, suggesting an allosteric mechanism of action.The presumed allosteric site was validated via a 3.15 cocrystal structure of 1 in complex with IL-17A.Furthermore, functional studies demonstrated that engagement of this allosteric pocket by 1 potently inhibited IL-17A-induced G-CSF production in primary human keratinocytes, thereby establishing its pharmacological relevance.An SAR campaign, utilizing the crystal structure, allowed the authors to identify compound 3, which showed improved affinity in the biophysical and biochemical assays as well as a 10-fold improvement in the cell-based assay.