Identification of a new protein-RNA interaction inhibitor targeting the KH34 region of the insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2/IMP2)

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2/IMP2) plays a crucial role in the posttranscriptional regulation of gene expression and influences various cellular processes including cell growth, differentiation, and metabolism. Dysregulation of IMP2 has been associated with several diseases, including cancer and metabolic disorders. Targeting IMP2 with small molecules is a promising therapeutic strategy. However, the structural diversity of IMP2-targeting compounds remains limited. In this study, we present a comprehensive screening approach with the aim of identifying new structural classes of compounds that can inhibit IMP2 activity, particularly its binding to the KH34 domain. Screening of a chemically diverse library comprising 10,240 compounds using fluorescence polarization-based assays led to the identification of ten primary actives belonging to five distinct structural classes. After rigorous resynthesis and hit validation, only one compound comprising a sulfonamide scaffold reproducibly inhibited the KH34-RNA interaction in vitro. This hit was further characterized by STD-NMR and in vitro ADME profiling, including solubility, lipophilicity, metabolic stability, plasma protein binding, and cellular permeability. While this sulfonamide-based inhibitor exhibits clear biochemical activity and a defined binding mode at the KH34 RNA-binding interface, its limited cellular permeability and high plasma protein binding currently preclude cellular efficacy. This work identifies a new structural class of IMP2 KH34 inhibitors serving as a starting point for an ongoing hit-to-lead optimization campaign towards next-generation anti-cancer drugs.