DI-1548

DI-1548 is a potent, selective, irreversible covalent inhibitor of DCN1 (IC50 = 4.6 nM) . It efficiently and selectively inhibits the neddylation of Cullin 3 at nanomolar concentrations without significantly affecting the neddylation of other Cullin proteins, such as Cullin 1, 2, 4A, 4B, and 5, and exhibits no cytotoxicity. The covalent bond formation between DI-1548 and DCN1 disrupts the DCN1-UBC12 interaction, leading to the disassembly of the neddylation complex and the subsequent inactivation of CRL3. This process results in the accumulation of NRF2 and the upregulation of its target genes, providing hepatoprotective effects in mouse models. DI-1548 is applicable in studies related to liver injury.