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
Ashley L. Ramos, Eric R. Goedken, Kristine E. Frank, M.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 M. Phelan, Wei Qiu, J. Brad Shotwell, Anurupa Shrestha, Myron Srikumaran, Zhi Su, Chaohong Sun, Anup K. Upadhyay, Michael D. Wood, Haihong Wu, Ruijie K. Zhang, Ying Zhang, Gang Zhao, Haizhong Zhu, Matthew P. Webster
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.