Ashley L. Ramos; Eric R. Goedken; Kristine E. Frank; Maria A. Argiriadi; Sana Bazzaz; Zhiguo Bian; Jesse T. C. Brown; Paolo A. Centrella; Hui-Ju Chen; Jeremy S. Disch; Pamela L. Donner; David B. Duignan; Diana Gikunju; Stephen N. Greszler; Marie-Aude Guié; Sevan Habeshian; Hajnalka E. Hartl; Christopher D. Hein; Charles W. Hutchins; Rachael Jetson; Anthony D. Keefe; Hasan Khan; Huan-Qiu Li; Allison Olszewski; Benjamin J. Ortiz Cardona; Augustine Osuma; Sanjay C. Panchal; Ryan Phelan; Wei Qiu; J. Brad Shotwell; Anurupa Shrestha; Myron Srikumaran; Zhi Su; Chaohong Sun; Anup K. Upadhyay; Michael D. Wood; Haihong Wu; Ruijie Zhang; Ying Zhang; Gang Zhao; Haizhong Zhu; Matthew P. Webster
J. Med. Chem., 2024, XXXX, XXX, XXX-XXX
https://doi.org/10.1021/acs.jmedchem.3c02397

Abstract

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.