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

• DOI: 10.1021/acsinfecdis.4c00864
• Publication Date: 2025-01-20T05:56:01Z
• Authors: Victoria Banas; Mostafa A. Elfawal; Bruce A. Rosa; Matthew Mahoney; Jacquelyn Kauffman; Emily Goetz; Paulina Chen; Raffi V. Aroian; Makedonka Mitreva; James W. Janetka

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