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 RamosEric R GoedkenKristine E FrankMaria A ArgiriadiSana BazzazZhiguo BianJesse T C BrownPaolo A CentrellaHui-Ju ChenJeremy S DischPamela L DonnerDavid B DuignanDiana GikunjuStephen N GreszlerMarie-Aude GuiéSevan HabeshianHajnalka E HartlChristopher D HeinCharles W HutchinsRachael JetsonAnthony D KeefeHasan KhanHuan-Qiu LiAllison OlszewskiBenjamin J Ortiz CardonaAugustine OsumaSanjay C PanchalRyan PhelanWei QiuJ Brad ShotwellAnurupa ShresthaMyron SrikumaranZhi SuChaohong SunAnup K UpadhyayMichael D WoodHaihong WuRuijie K ZhangYing ZhangGang ZhaoHaizhong ZhuMatthew P WebsterPublished in: Journal of medicinal chemistry (2024)
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.