Targeting RNA-Binding Oncofetal Protein IGF2BP3: Discovery of Potent and Selective Inhibitors.

Cancer remains a major global health burden and a leading cause of death worldwide, despite remarkable advances in cancer biology and therapeutics. RNA-binding proteins (RBPs) are an ideal target for cancer therapies due to their pivotal role in regulating gene expression. However, these proteins are notoriously difficult to target with small molecules, often being considered "undruggable". IGF2BP3 is one such protein, with a well-established oncogenic role across cancer types and cancer-specific expression patterns. Despite extensive biological evaluation of this protein over the last 30 years, efforts to develop a small-molecule inhibitor for this challenging, yet critical, target have only been rarely reported. We report a structure-activity relationship (SAR) campaign that allowed us to evaluate 37 analogs of I3IN-002, a compound previously shown to bind IGF2BP3. I3IN-002 and three of the most promising compounds identified were evaluated by a cellular thermal shift assay (CETSA) with results consistent with in-cell target engagement. Pharmacokinetic properties for these four compounds were also evaluated. Beyond enabling the discovery of several new potent and selective small molecules, these studies have allowed us to elucidate key parameters for potency, selectivity, and metabolic stability that should aid future efforts in RBP drug discovery.