– PROTAC NSD3 degrader-1 (compound 56) is a targeted degradation agent for the Nuclear receptor binding SET domain protein NSD3. It effectively induces NSD3 degradation in NCI-H1703 and A549 lung cancer cell lines, with DC50 values of 1.43 and 0.94 μM, respectively. Additionally, it hinders H3K36 methylation, triggers apoptosis, arrests the cell cycle, and diminishes the expression of NSD3-related genes, including CDC25A, ALDH1A1, and IGFBP.