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Publication Abstract from PubMed

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.

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.,Ramos AL, Goedken ER, Frank KE, Argiriadi MA, Bazzaz S, Bian Z, Brown JTC, Centrella PA, Chen HJ, Disch JS, Donner PL, Duignan DB, Gikunju D, Greszler SN, Guie MA, Habeshian S, Hartl HE, Hein CD, Hutchins CW, Jetson R, Keefe AD, Khan H, Li HQ, Olszewski A, Ortiz Cardona BJ, Osuma A, Panchal SC, Phelan R, Qiu W, Shotwell JB, Shrestha A, Srikumaran M, Su Z, Sun C, Upadhyay AK, Wood MD, Wu H, Zhang R, Zhang Y, Zhao G, Zhu H, Webster MP J Med Chem. 2024 Apr 25;67(8):6456-6494. doi: 10.1021/acs.jmedchem.3c02397. Epub , 2024 Apr 4. PMID:38574366^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.