First Oral Small-molecule Inhibitors Designed by Generative AI Achieve Biologics-Like Pan-Inhibition of IL-17AA, AF, and FF Dimers 2309250

Abstract Introduction The most effective therapies for immunological diseases are injectable biologics that many patients cannot access and often prefer to avoid. There remains a strong need for safe and effective oral treatment options. Targeting clinically validated cytokine pathways with small molecule modulators provides a viable route to first-in-class oral medicines. IL-17A and IL-17F are key drivers of multiple autoimmune diseases, yet small-molecule inhibitors developed to date have been restricted to IL-17A and lack activity on IL-17F. Building on AI-generated scaffolds, we developed orally bioavailable small-molecule IL-17 inhibitors that potently block the full spectrum of IL-17A- and F-containing dimers. Methods Candidate inhibitors were engineered via AI-enabled structure-based generative design and virtual screening. Binding was confirmed and assessed by SPR and NanoDSF. Functional antagonism was quantified in cellular assays, with Ki values derived via agonist shift assays. In vivo activity was evaluated in IL-17-driven pharmacodynamic models. Oral pharmacokinetics was profiled across multiple preclinical species. Results Our lead inhibitors demonstrate high-affinity binding to all relevant isoforms and disrupt receptor engagement. They achieve Ki < 0.1 nM for IL-17A and < 10 nM for IL-17F in cellular assays. The activity on IL-17A is over 10-fold more potent than leading IL-17A-specific small molecules. These inhibitors demonstrate favorable oral bioavailability and dose-dependently suppress IL-17F—driven cytokine production in vivo, achieving maximal inhibition levels comparable to the dual-specific antibody bimekizumab. Conclusion These data present the first orally bioavailable small molecules with strong IL-17F engagement, exceptional potency against all IL-17A and F dimers, and robust in vivo activity. By combining the efficacy of dual-cytokine blockade with the convenience of oral dosing, these inhibitors represent a potential best-in-class opportunity for next-generation autoimmune therapies. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)