Marcos E. Milla, Jonathan M. Blevitt, Steven D. Goldberg, Anthony A. Armstrong, Katherine Y. Blain, Krystal Herman, Annie X. Liu, Rosa Luna, Cynthia Milligan, Aaron Patrick, Ruth Steele, Scott D. Bembenek, Paolo Centrella, Matthew A. Clark, John W. Cuozzo, Jeremy S. Disch, Diana Domingo, Avery Hunt, C.D. Hupp, Anthony D. Keefe, Jinquan Luo, Tara Mirzadegan, Marina I. Nelen, Daniel I. Resnicow, Eric A. Sigel, Holly H. Soutter, Dawn M. Troast, Xiaohua Xue, Yi Fang, Ying Zhang, Paul Jackson, James P. Edwards, Kevin J. Lumb
A novel series of inhibitors of the interaction of IL-17A with its cognate receptor has been discovered using DNA-encoded library (DEL) technology. The lead compound (JNJ627, Compound 1 ) 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.