Abstract

E3 ligases are crucial to PROTAC technology, and identifying novel E3 ligase ligands could accelerate the advancement of PROTACs. DCAF11 has shown considerable potential for PROTAC applications. However, the ligands targeting DCAF11 remain limited, highlighting the need for the development of novel ligands for this E3 ligase. In this study, leveraging previous research on DCAF11 ligands, we designed a class of arylidene-thiazoldione scaffolds and applied it to develop PROTACs, resulting in the identification of a potent BRD4 degrader, LGF308. Degradation activity and mechanistic studies demonstrated that the compound LGF308 efficiently induces BRD4 degradation through the proteasomal pathway and via recruitment of DCAF11. This scaffold represents a reliable ligand, capable of facilitating the degradation of various proteins, including CDK4/6, BTK, and FKBP12. Therefore, this study introduces the arylidene-thiazoldione scaffold as a novel DCAF11 ligand and validates its application in PROTAC design, providing strong support for the development of DCAF11-based PROTACs.