Development of the first-in-class diabetes drug, PS1

Over 430 million people suffer from type 2 diabetes (T2D) worldwide. It causes 5 million deaths annually. T2D is now incurable. Thus, there is an urgent need to seek a new method to treat and/or reverse T2D. Functional islet cells die over time during T2D development, leading to an irreversible status. Recently, maintenance of islet mass and function is emerging as a new strategy to cure T2D. However, the mechanism of this maintenance is unclear. Our unpublished data demonstrated that PX, the largest PDI with 3 CGHC motifs, was primarily expressed in in islet cells. Further, we show that PX increased in response to nutrient overload and diabetes. Therefore, PX can be used as a diagnostic marker for diabetes. More importantly, PX knockout and transgenic overexpression in animal manifested that PX positively regulated β-cell pathogenesis and T2D. Furthermore, mechanistic studies showed that PX promoted T2D via ROS pathway-mediated ROS generation in β-cells. Therefore, PX can be used as a drug target for T2D. As a result, PS1, one of PX inhibitors, reduced β-cell pathogenesis and T2D. There are three aims in this project, including 1) perform chemistry, manufacturing and control, 2) non-clinical safety study, and 3) pharmacokinetics study of PS1. Such study can eventually complete the preclinical data required for the investigational drug application of PS1. This study was sponsored by MOST and is under way to finalize preclinical data and IND application.