Marcos E. Milla; Jonathan M. Blevitt*; Steven D. Goldberg;Anthony A. Armstrong;Katherine Y. Blain;Krystal L. Herman;Annie X. Liu;Rosa Luna;Cynthia M. Milligan;Aaron N. Patrick;Ruth A. Steele;Scott D. Bembenek;Paolo Centrella;Matthew A. Clark;John W. Cuozzo;Jeremy S. Disch;Derrick Domingo;Avery Hunt;Christoper 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 XueFang Yi;Ying Zhang;Paul F. Jackson;James P. Edwards;Kevin J. Lumb

ACS Med. Chem. Lett. 2025, XXXX, XXX, XXX-XXX

https://doi.org/10.1021/acsmedchemlett.5c00502

Abstract

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.