A Novel Small Molecule Allosteric Inhibitor of IL-17A from a DNA-Encoded Library

) of the series occupies the interior interface of the IL-17A homodimer and disables receptor binding. The mechanism of action involves allosteric disruption of the IL-17A quaternary structure to prevent adoption of the receptor-binding conformation, rather than direct orthosteric inhibition at the receptor-binding site. Molecules of this series exhibit remarkably slow on-rate kinetics and potent inhibition of IL-17A signaling in human primary cells.