The Development of TGR5 Antagonists for the Treatment of Cholangiopathies

PROJECT NARRATIVE Polycystic liver disease (PLD) is an incurable rare genetic condition related to a family of diseases called cholangiopathies, in which cysts grow in the liver, and which can lead to impaired liver function, chronic pain, and in some cases liver failure (requiring transplantation) or renal failure (requiring dialysis and/or kidney transplantation). Collaborators on this proposal: 1) discovered a pathway implicated in the development of hepatic cysts in PLD as well as in bile duct cancer (cholangiocarcinoma) and other non-biliary cancers (breast, gastric, pancreas), 2) linked this pathway to a druggable target, and 3) screened against this target to find chemical starting points (leads). This proposal seeks to optimize these novel small molecule leads towards therapeutics for cholangiopathies and further elucidate the biology of PLD.