DOP64 Discovery of highly selective small-molecule oral inhibitors of integrin α4β7 for the treatment of inflammatory bowel diseases

Abstract

Abstract Background Integrins play a key role in facilitating immune cell trafficking throughout the body and represent an important receptor family for therapeutic intervention. In particular, the α4β7 integrin is a clinically validated target for the treatment of inflammatory bowel diseases (IBD), as exemplified by the humanised monoclonal antibody vedolizumab, which blocks the interactions between α4β7-expressing lymphocytes and its ligand MAdCAM-1. This blockade leads to the inhibition of these circulating lymphocytes from exiting the bloodstream and entering intestinal mucosal tissues resulting in a decrease in mucosal inflammation in patients. While oral inhibitors of the α4β7 integrin are advantageous over biologics, the efforts have been impeded by challenges to achieve desired selectivity and optimal DMPK properties. The aim of this study was to develop and characterise orally bioavailable small-molecule inhibitors of the α4β7 integrin and to determine their therapeutic potential. Methods Oral small-molecule inhibitors targeting the α4β7 integrin were discovered using Morphic Integrin Technology (MInT) platform. These small-molecule inhibitors were tested for potency and selectivity against a broad panel of integrin family members in multiple biochemical and cell-based functional assays in a ligand-competitive fashion. An acute PD assay with CFSE-labelled lymphocytes was developed to evaluate the activity of the small-molecule compounds in blocking lymphocyte trafficking to gut-associated lymphoid tissues in mice. The in vivo activity was also examined through changes in circulating α4β7+ CD4+ T memory cells in a relevant non-human primate model. Results Key drug candidate small molecules demonstrated over 1000-fold selectivity in vitro against a broad panel of integrin family members, including the α4β1 integrin. These compounds effectively blocked lymphocyte trafficking to mesenteric lymph nodes and Peyer’s patches in the gut in a dose-dependent manner, similar to an α4β7-specific antibody, in an acute gut-homing assay in mice. Additionally, these inhibitors also demonstrated effective occlusion of immune trafficking in a relevant non-human primate model. The lead compound has favourable DMPK properties, good oral bioavailability and is projected to have sufficient exposure in humans to effectively block α4β7-expressing immune cells in circulation. Conclusion Potent, selective, oral small-molecule inhibitors of α4β7 integrin have been discovered that demonstrate on-target, mechanistic efficacy in two animal models relevant to human IBD. It has the potential to be an effective and safe therapeutic in monotherapy as well as serving as a backbone for combination with other IBD drugs.