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

• Published in: Journal of medicinal chemistry Vol. 67; no. 8; pp. 6456 - 6494
• Main Authors: Ramos, Ashley L., Goedken, Eric R., Frank, Kristine E., Argiriadi, Maria A., Bazzaz, Sana, Bian, Zhiguo, Brown, Jesse T. C., Centrella, Paolo A., Chen, Hui-Ju, Disch, Jeremy S., Donner, Pamela L., Duignan, David B., Gikunju, Diana, Greszler, Stephen N., Guié, Marie-Aude, Habeshian, Sevan, Hartl, Hajnalka E., Hein, Christopher D., Hutchins, Charles W., Jetson, Rachael, Keefe, Anthony D., Khan, Hasan, Li, Huan-Qiu, Olszewski, Allison, Ortiz Cardona, Benjamin J., Osuma, Augustine, Panchal, Sanjay C., Phelan, Ryan, Qiu, Wei, Shotwell, J. Brad, Shrestha, Anurupa, Srikumaran, Myron, Su, Zhi, Sun, Chaohong, Upadhyay, Anup K., Wood, Michael D., Wu, Haihong, Zhang, Ruijie, Zhang, Ying, Zhao, Gang, Zhu, Haizhong, Webster, Matthew P.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.04.2024; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; DNA - chemistry; DNA - metabolism; Drug Discovery; Humans; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - metabolism; Life Sciences & Biomedicine; Mice; Pharmacology & Pharmacy; Protein Binding; Science & Technology; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; KETONES; SECUKINUMAB; PSORIASIS; PREDICTION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c02397

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.