Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds

Dysregulation of IL17A drives numerous inflammatory and
autoimmune
disorders with inhibition of IL17A using antibodies proven as an effective
treatment. Oral anti-IL17 therapies are an attractive alternative
option, and several preclinical small molecule IL17 inhibitors have
previously been described. Herein, we report the discovery of a novel
class of small molecule IL17A inhibitors, identified via a DNA-encoded
chemical library screen, and their subsequent optimization to provide
in vivo efficacious inhibitors. These new protein–protein interaction
(PPI) inhibitors bind in a previously undescribed mode in the IL17A
protein with two copies binding symmetrically to the central cavities
of the IL17A homodimer.