Developing novel inhibitors of the gut microbiome to modulate drug metabolism

The long term objective of this project is a therapeutic adjunct to prevent adverse gastrointestinal eventsincluding life threatening diarrheaassociated with Ofevand Stivargaused to treat idiopathic pulmonary fibrosis and metastatic colorectal cancerrespectivelyAdverse GI events associated with both drugs is a major reason for reducingpostponingor stopping treatmentthus compromising efficacyOne fundamental and common source of drug dependent lower GI adverse events is microbiome mediated drug metabolismduring which commensalglucuronidase enzymesGUSreactivate drug metabolites in the gutWe previously demonstrated the therapeutic efficacy of GUS enzyme inhibition as a novelSymbiotic Drugapproach to ameliorate gastrointestinal sequela associated with common anti inflammatory drugs and the chemotherapeutic agentirinotecanHerewe aim to identify novel symbiotic drugs to increase the efficacy of Ofev and Stivargawhile simultaneously reducing the risk of side effectsWe previously developed a rapid screening assay that uses a clinically relevant source of GUS enzymesand demonstrated that Ofev and Stivarga metabolites are substrates for bacterial GUS enzymesIn Phase I we will optimize our assay for high throughput screening for novel GUS inhibitorsIn Phase IIwe will commence a high throughput screenidentify lead candidate GUS inhibitorsand define the symbiotic drug candidacy of eachA key deliverable in the proposed project is a lead drug series for both Ofev and Stivargawhich will be evaluated for efficacy and safety in future pre clinical animal studiesWe expect that the development and validation of a comprehensive class of GUS inhibitors will be broadly applicable to improve the therapeutic index of many existing drugs This project aims to discover and develop microbiome targeting therapeutics that selectively block the activity of a bacterial enzyme responsible for triggering the debilitating and sometimes deadly diarrhea that can occur in patients using Ofevused to treat idiopathic pulmonary fibrosisand Stivargaused to treat metastatic colorectal cancerThis project builds on a unique microbiome targeted approach to enhance the quality of life of patients using these drugs