Structure-Guided Design of Intestine-Selective AHR Agonists for Restoration of Gut Barrier Integrity in IBD

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Project Summary At least one-third of patients with inflammatory bowel disease (IBD) do not respond appropriately to existing therapies and conventional agents remain limited by an increased risk of infection or malignancy, anti- drug antibodies, and high cost. Recent evidence now suggests that the exacerbated inflammatory response observed in IBD is initiated and maintained by loss of gut epithelial integrity with an ensuing dysbiosis and accompanying bacterial translocation and invasion. Crucial to the maintenance of epithelial barrier integrity, as well as gut microbial homeostasis and protection from pathogenic microorganisms is the mucosal immune system. The aryl hydrocarbon receptor (AHR) is an essential regulator of the gut immune system and mediates processes, including the expression of IL-22, which are responsible for gut tissue integrity, epithelial repair, and microbial homeostasis. We have recently discovered a new class of highly potent and drug-like AHR agonists derived from an indole-pyridine scaffold, which are suitable for oral administration and display promising pharmacokinetic (PK) and pharmacodynamics profiles. In this proposal we intend to: (1) Determine the modes of action of first-generation AHR agonists based on an indole-pyridine scaffold in complementary models of gut barrier dysfunction. In the first phase of our investigations, we will define the extent to which first-generation drug candidates mediate intestinal repair by modulating either the mucosal immune response or through a direct effect on the epithelium in complementary mouse models of enteritis. In the second phase, the ability of lead drug candidates to enhance intestinal integrity will be further evaluated using primary gut organoids, as well as through the use of gut organoid/immune cell co-culture models. (2) Design of intestine-selective AHR agonists with limited systemic exposure. We believe that design strategies that limit systemic activation of AHR will further enhance the safety profile of this important class of compounds. Our established lead compounds will be used as parent structures to explore the incorporation of substituents, as well as the design of antedrugs, which reduce systemic exposure. The druggable chemical space will be defined to ensure successful identification of gut-selective AHR agonists that display preferential activation of AHR in intestinal tissue with limited systemic exposure. We will confirm IL-22 induction in human T cells from healthy adults and adults with active IBD. (3) Characterize the effectiveness of intestine-selective AHR agonists in murine models of gut barrier dysfunction. Defining the therapeutic efficacy of intestine-selective AHR agonists for the prevention and treatment of IBD will be focus of the initial phase of these studies. Compound efficacy will be assessed in additional complementary murine models of enteritis in both prevention and intervention protocols. We will subsequently determine the safety profile, including genotoxicity, off-target selectivity, and dose-dependent toxicity for lead gut-selective compounds, which demonstrate significant in vivo potency and efficacy.