Development and Characterization of Small Molecule Chemical Probes for Alzheimer's Disease‐associated Human RNA Helicases

We present a robust high-throughput in vitro assay designed for small molecule screening in a 384-well format, enabling hit optimization and facilitating the discovery of inhibitors for MDA5, LGP2, and DDX1. Through DEL-ML screen, we identified a selective MDA5 inhibitor that can be used to further interrogate its role in AD pathogenesis, and serve as a chemical starting point for future drug discovery efforts. This ligand represents first-in-class small molecule inhibitor for MDA5, a target that has been underexplored in the context of its role in AD.