Discovery of Human PIM Kinase Inhibitors as a Class of Anthelmintic Drugs to Treat Intestinal Nematode Infections.

Abstract

Soil-transmitted helminth (STH) infections affect one-fourth of the global population and pose a significant threat to human and animal health, with limited treatment options and emerging drug resistance. Trichuris trichiura (whipworm) stands out as a neglected disease, necessitating new drugs to address this unmet medical need. We discovered that several different chemical series of related human Provirus Integration sites for Moloney murine leukemia virus (PIM) family kinase inhibitors possess potent anthelmintic activity by using whole-worm motility assays. Systematic structure-activity relationship (SAR) studies based on the pan-PIM kinase inhibitor CX-6258 were conducted to identify compounds displaying improved in vitro motility inhibition of both adult hookworm (Ancylostoma ceylanicum) and adult whipworm (Trichuris muris) nematodes. A broad kinase selectivity screen of >450 human kinases confirms PIM1 kinase and others as potential targets for CX-6258 and analogues thereof. In addition, we demonstrated that CX-6258 significantly reduced worm burden and egg counts in the T. muris infection model of mice, establishing it as a new oral small molecule anthelmintic therapeutic.