Characterization of Small Molecule Inhibitors of CLKs and DYRKs

Abstract

Colorectal cancer (CRC) used to be known as a disease of old age, but now it is becoming a concern for younger adults. Researchers are unsure why, but they believe it may be due to environmental factors that lead to genetic changes in the colonic epithelium. These genetic changes affect essential signaling pathways, making them a crucial research focus. The Wnt signaling pathway is significant in maintaining digestive tract homeostasis but is often dysregulated in cancer. For this reason, researchers are working to identify proteins that affect Wnt signaling and target them with inhibitors. The CLK and DYRK kinase families are a group of proteins closely linked to the Wnt signaling pathway and implicated in disease. In this study, I tested 107 novel small molecules that are CLK/DYRK inhibitors in a dose-response curve with human colonic epithelial cells (HCECs). From this data, we identified six top compounds that were tested further in a cell viability assay to determine their efficacy against cancer cells. We also immunoblotted for CLKs' substrate to understand how the compounds work and obtained pharmacokinetic data to understand their biomechanics. Ultimately, two promising compounds emerged as potential candidates for further organoid profiling – DYR726 and DYR895. We are especially excited for DYR895 to be FDA-approved soon, but we will also further assess DYR726