AI/ML-Accelerated Discovery of Oral α4β7 Integrin Inhibitors for Treating Inflammatory Bowel Disease 2327698

Abstract Introduction Integrins are essential cell-adhesion receptors; α4β7 mediates gastrointestinal homing of lymphocytes via MAdCAM-1 on gut endothelium. Inflammatory bowel disease (IBD) involves pathogenic infiltration of α4β7-positive T cells. Blocking α4β7 reduces intestinal inflammation, as demonstrated by the clinical efficacy of the therapeutic antibody vedolizumab. However, limitations of antibody therapy underscore the need for selective, orally available small-molecule α4β7 inhibitors. Methods We leveraged deep disease expertise and our AI/ML-driven drug discovery platform to accelerate progress toward the discovery of novel oral α4β7 inhibitors for IBD. Our modular, highly configurable platform orchestrates commercial and proprietary tools within a high-performance computing infrastructure and integrates optimized design—make—test—analyze cycles for compound optimization. These cycles are supported by a comprehensive screening cascade comprising multiple tiers of target- and indication-relevant assays, including non-cellular, in vitro assays, translational and in vivo models. Results Leveraging extensive literature data, and predictive modeling, we advanced from target identification to novel lead compounds in under 18 months. To maximize success and accelerate progress, we implemented multiple parallel and complementary strategies. The resulting promising compounds demonstrated potency and high selectivity for α4β7 over α4β1 in translational assays and in vivo models. Conclusion Our AI/ML-driven drug discovery platform enabled rapid progression to advanced oral α4β7 inhibitor leads with strong preclinical validation. These results demonstrate the power of our integrated approach to significantly accelerate timelines in small-molecule discovery. This strategy is broadly applicable beyond α4β7, offering a versatile solution for delivering innovative therapies. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)