• Novel WNT/beta-catenin Signaling Pathway Inhibitors for the Treatment of Metabolic Disorders

      Obianom, Obinna N.; Shu, Yan, Ph.D. (2018)
      The WNT/β-catenin signaling (β-cat) pathway is critical for embryonic development and tissue homeostasis. For this reason, alterations in the β-cat pathway are associated with many ailments including metabolic disorders, which may result from defects in the energy metabolism. The contribution of β-cat pathway to energy metabolism has become a subject of many investigations following the identification of polymorphisms in β-cat pathway components that predispose individuals to type-2-diabetes. Current evidence suggests that downregulation of the β-cat pathway activity may help treat metabolic disorders. Given these findings, the overarching goal of this thesis was to discover and develop novel β-cat pathway inhibitors and to examine their efficacy on glucose and lipid metabolism. We started with an FDA approved anthelmintic, pyrvinium, which is a potent inhibitor of the β-cat pathway. Our results showed that pyrvinium improved glucose tolerance by inhibiting glucose output, hepatic lipid accumulation and activating the AMPK pathway. Despite these beneficial effects, pyrvinium is unsuitable for repurposing to use orally in the treatment of metabolic disorders due to its almost zero bioavailability and other unspecific toxic effects in mice at higher doses. Based on the structure of pyrvinium, we decided to discover new potent β-cat pathway inhibitors with lower toxicity and improved bioavailability. Our screening of more than 150 newly synthesized pyrvinium derivatives led to the discovery of YW1128 as such a candidate having the aforementioned properties. Administration of YW1128 led to decreased lipid accumulation and improved glucose tolerance in the mice fed with high fat diet. Previous studies had suggested a critical role of hepatic β-cat pathway in determining the whole body metabolic homeostasis. So we next sought to achieve a selective delivery of the new derivatives to the liver without having significant disposition in other tissues. We performed a proof-of-concept study where we took advantage of high expression of organic cation transporter 1 (OCT1) in the liver to modify the compounds that were not specifically permeable to OCT1 expressing cells. We inserted a biguanide, which is a major backbone of several OCT1 substrates, into these compounds and showed that they became highly permeable to cells overexpressing OCT1. This suggests that insertion of the biguanide moiety into YW1128 may be an approach to improve its selective liver targeting. In conclusion, this thesis uncovered the efficacy by small molecule inhibition of β-cat pathway in the treatment of metabolic disorders and established that incorporating a biguanide moiety to the compounds may serve as a strategy to achieve selective liver targeting.