The findings that individuals with high-functioning autism shared similar but more severe impairments in verbal ToM than individuals with schizophrenia support the autism-schizophrenia continuum. The finding that verbal-based but not visual-based ToM was more impaired in high-functioning autism patients than schizophrenia patients could be attributable to the varied task/item difficulty between the two paradigms.

Background The interaction between the adhesion molecule MAdCAM-1 and the α4β7 integrin heterodimer enables the trafficking of gut-antigen specific lymphocytes to the small and large intestines and to gut-associated lymphoid tissues. The role of the α4β7 integrin in the pathophysiology of IBD has been clinically demonstrated, and targeted therapeutics have been shown to mitigate inflammation and mucosal damage mediated by α4β7+ lymphocytes. The purpose of this study was to determine the potency and selectivity of the small molecule α4β7 inhibitor GS-1069518. Methods The selectivity of GS-1069518 and relevant reference molecules was determined using in vitro cell capture assays with natural integrin ligands and by measuring receptor occupancy in human and cynomolgus monkey whole blood. The number of RPMI-8866 cells binding to MAdCAM-1-coated surfaces (a natural α4β7 ligand) and Jurkat cells binding to VCAM-1-coated surfaces (a natural α4β1 ligand) were quantified with high content imaging. Receptor occupancy on CD3+CD4+CD45RO+β7+ (human) or CD3+CD4+CD45RA-β7+ (cynomolgus monkey) and CD3+CD4+CD45RO+α4+β1+β7- (human) or CD3+CD4+CD45RA-α4+β1+β7- (cynomolgus monkey) memory T cells was measured by flow cytometry with fluorescent probes that detect occupancy in the ligand-binding sites. Results In a MAdCAM-1 cell capture assay, the EC50 of GS-1069518 was 0.034 nM, with 71-fold and >10,000-fold selectivity over α4β1 and αLβ2, respectively. In α4β7 receptor occupancy assays the EC50 of GS-1069518 was 0.36 nM in human whole blood and 0.4 nM in cynomolgus monkey whole blood. GS-1069518 was 482-fold selective for α4β7 over α4β1 in human whole blood and 119-fold selective for α4β7 in cynomolgus monkey blood. Conclusion GS-1069518 is a highly potent and selective small molecule inhibitor of the α4β7-MAdCAM-1 ligand binding interaction.