Final Report Summary - DIDO (Innovative drugs targeting IDO molecular dynamics in autoimmunity and neoplasia)
The aim of DIDO was to develop novel drugs capable of acting over the long term by either favoring (thus useful in the therapy of chronic inflammation and autoimmune disease) or inhibiting (useful in neoplasia) the IDO1 signaling. To this purpose, the expertise in pharmacology/immunology/biology (PI’s group) has been integrated with the expertise in medicinal chemistry/molecular and computational modeling (team member’s group) to develop such innovative drugs. During the lifetime of the project, we established a novel, integrated method capable of screening hundreds of compounds with the potential of modulating IDO1 signaling. We screened more than 200 structurally diverse compounds selected from a structure-based virtual screening of about 600.000 small molecules endowed with drug-like or lead-like properties. Of these, 10 compounds were so far proven to be novel, potent IDO1 catalytic inhibitors. We also identified chemical structures capable of modulating the signaling and not catalytic activity of IDO1. Specifically, one of these, VIS-110, did not show significant inhibitory effects on IDO1 catalysis but did promote the IDO1 signaling and, when used in DC cultures, conferred long-term tolerogenic properties capable of blocking the presentation of an autoantigen in vivo in an IDO1-dependent fashion. More importantly, administration of VIS-110 in vivo protected mice from experimental autoimmune encephalomyelitis, an experimental model of human multiple sclerosis. These data led to obtain an ERC-POC grant. One VIS-110 analogue, i.e. VIS-128 instead showed inhibitory effects on the IDO1 signaling pathway, which may be relevant in cancer immunotherapy. We unexpectedly discovered IDO1 catalytic enhancers, i.e. VIS-119 and the more potent VIS-329, capable of increasing the affinity of IDO1 for its substrate, tryptophan, in both cell and biochemical (using a recombinant IDO1 protein) assays. VIS-119 was also effective in protecting mice from the development of experimental autoimmune encephalomyelitis in a mode of action requiring IDO1 but also the immunoregulatory receptor AhR, which can indeed be activated by kynurenine, the main IDO1 product. We also succeeded in obtaining the crystal of VIS-329 with IDO1, unveiling a new positive allosteric site in the enzyme. Finally, we identified several novel IDO1 catalytic inhibitors acting in the nM-low µM range that will be used in tumor models to prove their efficacy. The selected molecules have been subjected to studies of structure activity relationships, early ADME profiling, pharmacokinetics, and toxicity, indicating an overall pharmacokinetic and toxicity profile.