Aryl Aldehyde-anchored Small Molecules Recruit FBXO22 for Targeted Degradation of NSD2

Targeted protein degradation (TPD) has emerged as a transformative strategy in drug discovery, yet the repertoire of E3 ligase recruiters remains limited. Here, we report the discovery of an aldehyde-anchored PROTAC that covalently engages the E3 ligase FBXO22 to induce degradation of the histone methyltransferase NSD2. A phenyl aldehyde warhead was identified as optimal through competitive electrophile screening, and structure–activity relationship studies indicated that degradation is highly sensitive to steric and electronic features surrounding the aldehyde moiety. The optimized degrader, compound T9, effectively induced NSD2 degradation across multiple cancer cell lines, and subsequent mechanistic investigations confirmed that degradation is dependent on FBXO22, the ubiquitin–proteasome system, and the neddylation pathway. Mutagenesis identified Cys326 in the FBXO22 C-terminal domain as critical for activity. Collectively, this work establishes a stable covalent ligand for FBXO22 recruitment and expands the chemical space of PROTAC design by introducing a readily accessible aldehyde-based E3 ligase ligand with broad potential for targeted protein degradation.